DE60025747T2 - NEW BENZIMIDAZOLE DERIVATIVES USE AS ANTIPROLIFERATIVE AGENTS - Google Patents

Description

The The present invention relates to novel benzimidazole derivatives which are disclosed in U.S. Pat the treatment of abnormal cell growth, such as cancer, useful in mammals are. This invention further relates to a method of use such compounds in the treatment of abnormal cell growth in mammals, in particular humans, and pharmaceutical compositions containing contain such compounds.

It is known to be a cell due to the transformation of a Part of their DNA to an oncogene (i.e., a gene that when activated leads to the formation of malignant tumor cells) can become cancerous. Many oncogenes encode proteins that are aberrant tyrosine kinases, cell transformation can cause. Alternatively, the overexpression a normal proto-oncogenic tyrosine kinase also leads to proliferative disorders, which sometimes lead to a malignant phenotype.

receptor are enzymes that span the cell membrane and an extracellular binding domain for growth factors, like epidermal growth factor, a transmembrane domain and a intracellular Part that acts as a kinase under Phosphoqqrylierung specific tyrosine residues in proteins and therefore influencing cell proliferation works, have. Other receptor tyrosine kinases include c-erbB-2, c-met, tie-2, PDGFr, FGFr and VEGFR. It is known that such kinases with frequent human cancers, such as breast cancer, gastrointestinal cancer, such as colon, rectum or stomach cancer, leukemia and ovarian, bronchial or pancreatic cancer, often aberrantly expressed. It is also known that epidermal growth factor receptor (EGFR), tyrosine kinase activity possesses, in many human cancers, such as brain, lung, Squamous, bladder, stomach, breast, head and neck, esophagus, gynecological and thyroid tumors, is mutated and / or overexpressed becomes.

Therefore It was recognized that inhibitors of receptor tyrosine kinases as selective Inhibitors of growth of mammalian cancer cells are usable. For example, erbstatin, a tyrosine kinase inhibitor, weakens selectively the growth of a transplanted human breast carcinoma, the one epidermal growth factor receptor tyrosine kinase (EGFR) expressed in nude mice with Athymie, however, it has no effect on the growth of another Carcinoma that does not express the EGF receptor. Therefore, the Compounds of the present invention, the selective inhibitors certain receptor tyrosine kinases, in particular PDGFr, are in the treatment of abnormal cell growth, especially cancer mammals usable.

Various other compounds, such as styrene derivatives, have also been shown to possess tyrosine kinase inhibitory properties. More recently, there are five European patent publications, namely EP 0 566 226 A1 (published on October 20, 1993), EP 0 602 851 A1 (published June 22, 1994), EP 0 635 507 A1 (published on January 25, 1995), EP 0 635 498 A1 (published on January 25, 1995) and EP 0 520 722 A1 (published December 30, 1992), certain bicyclic derivatives, especially quinazoline derivatives, which possess anti-cancer properties that are a consequence of their tyrosine kinase inhibitory properties. Further, International Patent Application WO 92/20642 (published November 26, 1992) relates to certain bis-mono- and bicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitors useful for inhibiting aberrant cell proliferation. International Patent Applications WO 96/16960 (published Jun. 6, 1996), WO 96/09294 (published Mar. 6, 1996), WO 97/30034 (published August 21, 1997), WO 98/02434 (published Jun. 22, 1997) , Jan. 1998), WO 98/02437 (published January 22, 1998) and WO 98/02438 (published January 22, 1998) also relate to substituted bicyclic heteroaromatic derivatives as tyrosine kinase inhibitors which are useful for the same purpose.

Please refer also WO 99/16755, J. Med. Chem. 1998, 41, 5457-5465, and J. Med. Chem. 1999, 42, 2373-2382.

Summary the invention

pharmazeutisch akzeptable Salze, Prodrugs und Solvate derselben, worin:
X CH oder N bedeutet;
R¹ aus -(CR⁴R⁵)_tC(O)OR³, -(CR⁴R⁵)_tC(O)NR³R⁴, -(CR⁴R⁵)_tOR³, -(CR⁴R⁵)_tC(O)(C₃-C₁₀-Cycloalkyl), -(CR⁴R⁵)_tC(O)(C₆-C₁₀-Aryl), -(CR⁴R⁵)_tC(O)(4- bis 10-gliedriges Heterocyclyl), -(CR⁴R⁵)_t(C₃-C₁₀-Cycloalkyl), -(CR⁴R⁵)_t(C₆-C₁₀-Aryl) und -(CR⁴R⁵)_t(4- bis 10-gliedriges Heterocyclyl), worin jedes t unabhängig voneinander eine ganze Zahl von 0 bis 5 ist, ausgewählt ist; wobei die Cycloalkyl-, Aryl- und Heterocyclyl-Einheiten von R¹ optional an einen Benzolring, eine C₅-C₈-Cycloalkylgruppe oder eine 4- bis 10-gliedrige heterocyclische Gruppe kondensiert sind; die -(CR⁴R⁵)_t-Einheiten der im Vorhergehenden genannten R¹-Gruppen optional eine Kohlen stoff-Kohlenstoff-Doppel- oder -Dreifachbindung umfassen, wenn t eine ganze Zahl zwischen 2 und 5 ist; die im Vorhergehenden genannten R¹-Gruppen optional mit 1 oder 2 Gruppen substituiert sind, die unabhängig voneinander aus -NR³R⁴, -OR³, C₁-C₁₀-Alkyl, C₂-C₁₀-Alkenyl und C₂-C₁₀-Alkinyl ausgewählt sind, wobei die Alkyl-, Alkenyl- und Alkinylgruppen mit 1 oder 2 Gruppen substituiert sind, die unabhängig voneinander aus -NR³R⁴ und -OR³ ausgewählt sind; und die im Vorhergehenden genannten R¹-Gruppen optional mit 1 bis 3 R²-Gruppen substituiert sind;
jedes R² unabhängig voneinander aus H, C₁-C₁₀-Alkyl, C₂-C₁₀-Alkenyl, C₂-C₁₀-Alkinyl, C₃-C₁₀-Cycloalkyl, Oxo, Halogen, Cyano, Nitro, Trifluormethyl, Difluormethoxy, Trifluormethoxy, Azido, -OR³, -C(O)R³, -C(O)OR³, -NR⁴C(O)OR⁶, -OC(O)R³, -NR⁴SO₂R⁶, -SO₂NR³R⁴, -NR⁴C(O)R³, -C(O)NR³R⁴, -NR⁵C(O)NR³R⁴, -NR³R⁴, -S(O)_j(CR⁴R⁵)_m(C₆-C₁₀-Aryl) , -S(O)_j(C₁-C₆-Alkyl), worin j eine ganze Zahl von 0 bis 2 ist, -(CR⁴R⁵)_m(C₆-C₁₀-Aryl), -O(CR⁴R⁵)_m(C₆-C₁₀-Aryl), -NR⁴(CR⁴R⁵)_m(C₆-C₁₀-Aryl), -O(CR⁴R⁵)_m(4- bis 10-gliedriger Heterocyclus), -NR⁴(CR⁴R⁵)_m(4- bis 10-gliedriger Heterocyclus), -(CR⁴R⁵)_m(4- bis 10-gliedriges Heterocyclyl) und -(CR⁴R⁵)_m(c₃-C₁₀-Cycloalkyl), worin jedes m unabhängig voneinander eine ganze Zahl von 0 bis 4 ist, ausgewählt ist; wobei die Alkyl-, Alkenyl- und Alkinylgruppen optional 1 oder 2 Heteroeinheiten enthalten, die aus O, -S(O)_j-, worin j eine ganze Zahl von 0 bis 2 ist, und -N(R³)- ausgewählt sind, mit dem Vorbehalt, dass zwei O-Atome, zwei S-Atome oder ein O- und ein S-Atom nicht direkt aneinander gebunden sind, und dem Vorbehalt, dass ein O-Atom, ein S-Atom oder ein N-Atom nicht direkt an eine Dreifachbindung oder eine nichtaromatische Doppelbindung gebunden ist; wobei die Cycloalkyl-, Aryl- und heterocyclischen Gruppen von R² optional an eine C₆-C₁₀-Arylgruppe, C₅-C₈-Cycloalkylgruppe oder 4- bis 10-gliedrige heterocyclische Gruppe kondensiert sind; und die Alkyl-, Cycloalkyl-, Aryl- und heterocyclischen Gruppen von R² optional mit 1 bis 5 Substituenten substituiert sind, die unabhängig voneinander aus Oxo (=O), Halogen, Cyano, Nitro, Trifluormethyl, Difluormethoxy, Trifluormethoxy, Azido, -NR⁴SO₂R⁶, -SO₂NR³R⁴, C(O)R³, -C(O)OR³, -OC(O)R³, -NR⁴C(O)OR⁶, -NR⁴C(O)R³, -C(O)NR³R⁴, -NR³R⁴, -OR³, C₁-C₁₀-Alkyl, -(CR⁴R⁵)_m(C₆-C₁₀-Aryl) und -(CR⁴R⁵)_m(4- bis 10-gliedriges Heterocyclyl), worin jedes m unabhängig voneinander eine ganze Zahl im Bereich von 0 bis 4 ist, ausgewählt sind;
jedes R³ unabhängig voneinander aus H, C₁-C₁₀-Alkyl, -(CR⁴R⁵)_m(C₆-C₁₀-Aryl) und -(CR⁴R⁵)_m(4- bis 10-gliedriges Heterocyclyl), worin jedes m unabhängig voneinander eine ganze Zahl von 0 bis 4 ist, ausgewählt ist; wobei die Alkylgruppe optional 1 oder 2 Heteroeinheiten umfasst, die aus O-, -S(O)_j-, worin j eine ganze Zahl im Bereich von 0 bis 2 ist, und -N(R⁴)- ausgewählt sind, mit dem Vorbehalt, dass zwei O-Atome, 2 S-Atome oder ein O- und ein S-Atom nicht direkt aneinander gebunden sind; die Cycloalkyl-, Aryl- und heterocyclischen Gruppen von R³ optional an eine C₆-C₁₀-Arylgruppe, C₅-C₈-Cycloalkylgruppe oder eine 4- bis 10-gliedrige heterocyclische Gruppe kondensiert sind; und die im Vorhergehenden genannten R³-Substituenten mit Ausnahme von H optional mit 1 bis 5 Substituenten substituiert sind, die unabhängig voneinander aus Oxo, Halogen, Cyano, Nitro, Trifluormethyl, Difluormethoxy, Trifluormethoxy, Azido, -C(O)R⁴, -C(O)OR⁴, -OC(O)R⁴, -NR⁴C(O)R⁵, -C(O)NR⁴R⁵, -NR⁴R⁵, Hydroxy, C₁-C₆-Alkyl und C₁-C₆-Alkoxy ausgewählt sind;
jedes R⁴ und R⁵ unabhängig voneinander H oder C₁-C₆-Alkyl bedeutet;
oder, wenn R⁴ und R⁵ an das gleiche Kohlenstoff- oder Stickstoffatom gebunden sind, R⁴ und R⁵ zusammengenommen mit dem Kohlenstoff oder Stickstoff einen 4- bis 10-gliedrigen Ring, der carbocyclisch oder heterocyclisch sein kann, bilden können;
jedes R⁶ aus den in der Definition von R³ angegebenen Substituenten ausgewählt ist, mit Ausnahme davon, dass R⁶ nicht H ist;
jedes R⁷, R⁸, R⁹, R¹⁰ und R¹¹ unabhängig voneinander aus der Gruppe von Substituenten, die in der Definition von R² angegeben sind, ausgewählt ist.The present invention relates to compounds of the formula 1

pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein:
X is CH or N;
R ^{1 is} - (CR ⁴ R ⁵ ) _t C (O) OR ³ , - (CR ⁴ R ⁵ ) _t C (O) NR ³ R ⁴ , - (CR ⁴ R ⁵ ) _t OR ³ , - (CR ⁴ R ⁵ ) _t C (O) (C ₃ -C ₁₀ -cycloalkyl), - (CR ⁴ R ⁵ ) _t C (O) (C ₆ -C ₁₀ -aryl), - (CR ⁴ R ⁵ ) _t C ( O) (4- to 10-membered heterocyclyl), - (CR ⁴ R ⁵ ) _t (C ₃ -C ₁₀ -cycloalkyl), - (CR ⁴ R ⁵ ) _t (C ₆ -C ₁₀ -aryl) and - ( CR ⁴ R ⁵ ) _t (4- to 10-membered heterocyclyl) wherein each t is independently an integer from 0 to 5; wherein the cycloalkyl, aryl and heterocyclyl moieties of R ^{1 are} optionally fused to a benzene ring, a C ₅ -C ₈ cycloalkyl group or a 4- to 10-membered heterocyclic group; the - (CR ⁴ R ⁵ ) _t units of the aforementioned R ¹ groups optionally comprise a carbon-carbon double or triple bond when t is an integer between 2 and 5; the abovementioned R ¹ groups are optionally substituted by 1 or 2 groups independently of one another selected from -NR ³ R ⁴ , -OR ³ , C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl and C ₂ - C ₁₀ alkynyl are selected, wherein the alkyl, alkenyl and alkynyl groups are substituted by 1 or 2 groups independently selected from -NR ³ R ⁴ and -OR ³ ; and the aforementioned R ¹ groups are optionally substituted with 1 to 3 R ² groups;
each R ^{2 is} independently selected from H, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₁₀ cycloalkyl, oxo, halogen, cyano, nitro, trifluoromethyl, Difluoromethoxy, trifluoromethoxy, azido, -OR ³ , -C (O) R ³ , -C (O) OR ³ , -NR ⁴ C (O) OR ⁶ , -OC (O) R ³ , -NR ⁴ SO ₂ R ⁶ , -SO ₂ NR ³ R ⁴ , -NR ⁴ C (O) R ³ , -C (O) NR ³ R ⁴ , -NR ⁵ C (O) NR ³ R ⁴ , -NR ³ R ⁴ , -S (O) _j (CR ⁴ R ⁵ ) _m (C ₆ -C ₁₀ aryl), -S (O) _j (C ₁ -C ₆ alkyl), wherein j is an integer from 0 to 2, - ( CR ⁴ R ⁵ ) _m (C ₆ -C ₁₀ aryl), -O (CR ⁴ R ⁵ ) _m (C ₆ -C ₁₀ aryl), -NR ⁴ (CR ⁴ R ⁵ ) _m (C ₆ -C ₁₀ -aryl), -O (CR ⁴ R ⁵ ) _m (4- to 10-membered heterocycle), -NR ⁴ (CR ⁴ R ⁵ ) _m (4- to 10-membered heterocycle), - (CR ⁴ R ⁵ ) _m (4- to 10-membered heterocyclyl) and - (CR ⁴ R ⁵ ) _m (c ₃ -C ₁₀ -cycloalkyl), wherein each m is independently an integer from 0 to 4; wherein the alkyl, alkenyl and alkynyl groups optionally contain 1 or 2 hetero units selected from O, -S (O) _j -, wherein j is an integer from 0 to 2, and -N (R ³ ) -, with the proviso that two O atoms, two S atoms, or one O and one S atom are not directly attached to each other, and the proviso that an O atom, an S atom, or an N atom is not directly is bonded to a triple bond or a non-aromatic double bond; wherein the cycloalkyl, aryl and heterocyclic groups of R ^{2 are} optionally fused to a C ₆ -C ₁₀ aryl group, C ₅ -C ₈ cycloalkyl group or a 4- to 10-membered heterocyclic group; and the alkyl, cycloalkyl, aryl and heterocyclic groups of R ^{2 are} optionally substituted with 1 to 5 substituents independently of one another selected from oxo (= O), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, NR ⁴ SO ₂ R ⁶ , -SO ₂ NR ³ R ⁴ , C (O) R ³ , -C (O) OR ³ , -OC (O) R ³ , -NR ⁴ C (O) OR ⁶ , -NR ⁴ C (O) R ³ , -C (O) NR ³ R ⁴ , -NR ³ R ⁴ , -OR ³ , C ₁ -C ₁₀ alkyl, - (CR ⁴ R ⁵ ) _m (C ₆ -C ₁₀ -Aryl) and - (CR ⁴ R ⁵ ) _m (4- to 10-membered heterocyclyl) wherein each m is independently an integer ranging from 0 to 4;
each R ^{3 is} independently H, C ₁ -C ₁₀ alkyl, - (CR ⁴ R ⁵ ) _m (C ₆ -C ₁₀ aryl) and - (CR ⁴ R ⁵ ) _m (4- to 10-membered heterocyclyl ), wherein each m is independently an integer of 0 to 4, is selected; wherein the alkyl group optionally comprises 1 or 2 hetero units selected from O-, -S (O) _j -, wherein j is an integer in the range of 0 to 2, and -N (R ⁴ ) -, with the proviso in that two O atoms, 2 S atoms or one O and one S atom are not directly bonded to each other; the cycloalkyl, aryl and heterocyclic groups of R ^{3 are} optionally fused to a C ₆ -C ₁₀ aryl group, C ₅ -C ₈ cycloalkyl group or a 4- to 10-membered heterocyclic group; and the abovementioned R ³ substituents, with the exception of H, are optionally substituted by 1 to 5 substituents independently of one another from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -C (O) R ⁴ , -C (O) OR ⁴ , -OC (O) R ⁴ , -NR ⁴ C (O) R ⁵ , -C (O) NR ⁴ R ⁵ , -NR ⁴ R ⁵ , hydroxy, C ₁ -C ₆ - Alkyl and C ₁ -C ₆ alkoxy are selected;
each R ⁴ and R ^{5 is} independently H or C ₁ -C ₆ alkyl;
or when R ⁴ and R ^{5 are} attached to the same carbon or nitrogen atom, R ⁴ and R ^{5 taken} together with the carbon or nitrogen can form a 4- to 10-membered ring which may be carbocyclic or heterocyclic;
each R ^{6 is selected} from the substituents specified in the definition of R ³ , except that R ^{6 is} not H;
each R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ^{11 is} independently selected from the group of substituents given in the definition of R ² .

In a specific embodiment, R ^{1 is} C ₆ -C ₁₀ -aryl or 4- to 10-membered heterocyclyl, wherein the aforementioned R ¹ groups are each substituted by 1 or 2 groups independently selected from -NR ³ R ⁴ , -OR ³ and C ₁ -C ₃ -alkyl, wherein the alkyl groups are substituted with 1 or 2 groups independently selected from -NR ³ R ⁴ and -OR ³ ; and the aforementioned R ¹ groups are optionally substituted with 1 to 3 R ² groups;
each R ^{2 is} independently H, C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, oxo (= O), -OR ³ , -C (O) R ³ , -C (O) OR ³ , -NR ⁴ C (O) R ³ , -C (O) NR ³ R ⁴ , -NR ³ R ⁴ , -NR ⁴ SO ₂ R ⁶ , -SO ₂ NR ³ R ⁴ , - (CR ⁴ R ⁵ ) _m (4- to 10-membered heterocyclyl) and (R ⁴ R ⁵ ) _m (C ₃ -C ₁₀ -cycloalkyl); and the alkyl groups optionally contain 1 or 2 hetero moieties selected from O, -S (O) _j -, wherein j is an integer from 0 to 2, and -N (R ³ ) -, with the proviso that two O atoms, two S atoms, or one O and one S atom are not directly bonded to each other; and the alkyl and cycloalkyl groups of R ² are optionally substituted with 1 to 5 substituents independently selected from oxo, cyano, trifluoromethyl, trifluoromethoxy, -NR ⁴ SO ₂ R ⁶ , -SO ₂ NR ³ R ⁴ , -C (O ) R ³ , -C (O) OR ³ , -NR ⁴ C (O) OR ⁶ , -NR ⁴ C (O) R ³ , -C (O) NR ³ R ⁴ , -NR ³ R ⁴ , -OR ³ and C ₁ -C ₁₀ alkyl, wherein each m is independently an integer in the range of 0 to 4.

In a further specific embodiment of the present invention, R ^{1 is} piperidinyl, piperazinyl or phenyl, where the R ¹ groups are substituted by -NR ³ R ⁴ , oxo (= O), -OR ³ and C ₁ -C ₃ -alkyl, wherein the alkyl group is optionally substituted with 1 or 2 groups independently selected from -NR ³ R ⁴ and -OR ³ ; and the aforementioned R ¹ groups are optionally substituted with 1 to 3 R ² groups.

In a further specific embodiment, the R ¹ groups are substituted by -NR ³ R ⁴ , oxo (= O), OR ³ or C ₁ -C ₃ -alkyl, wherein the alkyl group is substituted by -NR ³ R ⁴ .

In another specific embodiment of the present invention, R ^{1 is} phenyl substituted with pyrrolidin-1-yl, wherein the pyrrolidin-1-yl is optionally substituted with 1 to 3 substituents independently selected from oxo, cyano, trifluoromethyl, trifluoromethoxy, -NR ⁴ SO ₂ R ⁶ , -SO ₂ NR ³ R ⁴ , -C (O) R ³ , -C (O) OR ³ , -NR ⁴ C (O) OR ⁶ , -NR ⁴ C (O) R ³ , -C (O) NR ³ R ⁴ , -NR ³ R ⁴ , -OR ³ and C ₁ -C ₁₀ alkyl are selected; and R ¹¹ -OR ³ .

In particular, R ^{1 is} 4-pyrrolidin-1-ylmethylphenyl, which is optionally substituted with 1 to 3 substituents independently of one another from oxo, cyano, trifluoromethyl, trifluoromethoxy, -NR ⁴ SO ₂ R ⁶ , -SO ₂ NR ³ R ⁴ , -C (O) R ³ , -C (O) OR ³ , -NR ⁴ C (O) OR ⁶ , -NR ⁴ C (O) R ³ , -C (O) NR ³ R ⁴ , -NR ³ R ⁴ , -OR ³ and C ₁ -C ₁₀ alkyl are selected; and R ¹¹ -OR ³ .

In particular, R ^{11 is} connected to the 5-position of the benzimidazole unit of the compound of formula 1 and -OR ³ . In particular, R ^{11 is} attached to the 5-position of the benzimidazole moiety of the compound of formula 1 and 2-methoxyethoxy.

In another specific embodiment of the present invention, R ^{1 is} pyrrolidin-1-yl or piperidin-1-yl, wherein the R ^{1 is} optionally substituted with 1 to 3 substituents independently selected from oxo, cyano, trifluoromethyl, trifluoromethoxy, -NR ⁴ SO ₂ R ⁶ , -SO ₂ NR ³ R ⁴ , -C (O) R ³ , -C (O) OR ³ , -NR ⁴ C (O) OR ⁶ , -NR ⁴ C (O) R ³ , -C (O) NR ³ R ⁴ , -NR ³ R ⁴ , -OR ³ and C ₁ -C ₁₀ alkyl are selected.

In particular, R ^{1 is} pyrrolidin-1-yl or piperidin-1-yl substituted with -NR ³ R ⁴ and optionally substituted with 1 or 2 substituents independently selected from oxo, cyano, trifluoromethyl, trifluoromethoxy, -NR ⁴ SO ₂ R ⁶ , -SO ₂ NR ³ R ⁴ , -C (O) R ³ , -C (O) OR ³ , -NR ⁴ C (O) OR ⁶ , -NR ⁴ C (O) R ³ , C (O) NR ³ R ⁴ , -NR ³ R ⁴ , -OR ³ and C ₁ -C ₁₀ alkyl are selected; and R ¹¹ -OR ³ .

In particular, R ^{11 is} linked to the 5-position of the benzimidazole moiety of the compound of formula 1 and -OR ³ and R ⁹ and R ¹⁰ are both H.

In particular, R ^{11 is} linked to the 5-position of the benzimidazole moiety of the compound of formula 1, and 2-methoxyethoxy and R ⁹ and R ¹⁰ are both H.

Preferred compounds include those selected from the following group:
[1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine;
1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-ol;
1- {2- [5- (pyridin-2-ylmethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
{1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -dimethyl-amine;
{4- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -methyl-amine;
{4- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -dimethyl-amine;
Cyclopropyl- {4- [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -amine;
tert-butyl {4- [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -amine;
4- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] benzylamine;
1- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine;
{1- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -dimethyl-amine;
1- [2- (5-trifluoromethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine;
{4- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -methyl-amine;
Cyclopropyl- {4- [2- (5-ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -amine;
tert-butyl {4- [2- (5-ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -amine;
{4- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -dimethyl-amine;
1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-one;
1- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-one;
1- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ol;
tert-butyl {1- [2- (5-ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -amine;
{1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -methyl-amine;
2- (5-Methoxy-benzimidazol-1-yl) -8- (1-oxa-6-aza-spiro [2.5] oct-6-yl) -quinoline;
4-dimethylaminomethyl-1- [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ol;
1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -4-methylaminomethyl-piperidin-4-ol;
4-Aminomethyl-1- [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ol;
1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -pyrrolidin-3-ylamine;
1- (2-benzimidazol-1-yl-quinolin-8-yl) -piperidin-4-ylamine; 1- (2-imidazo [4,5-b] pyridin-3-yl-quinolin-8-yl) -piperidin-4-ylamine;
1- {2- [5- (4-methoxy-phenyl) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
1- [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine;
1- {2- [5- (3-Dimethylamino-propoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
1- {2- [5- (3-Amino-propoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
1- {2- [5- (2-Dimethylamino-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
1- {2- [5- (pyridin-4-ylmethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
1- [2- (5-Benzyloxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine;
1- {2- [5- (pyridin-3-ylmethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidine-4-carboxylic acid ethyl ester;
1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidine-4-carboxylic acid;
4-dimethylaminomethyl-1- [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ol;
N- {1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -acetamide;
N- {1- [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -acetamide;
1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ol;
{1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -urea;
4-Aminomethyl-1- {2- [5- (pyridin-2-ylmethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ol;
Cyclopropyl- (1- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) amine;
(1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -dimethyl-amine;
(1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -methyl-amine;
(1- {2- [5- (3-Dimethylamino-propoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -dimethyl-amine;
{1- [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -methyl-amine;
{1- [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -dimethyl-amine;
2-Amino-N- (1- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -acetamide;
- (S) -2-Amino-N- (1- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -propionamide;
- (R) -2-Amino-N- (1- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -propionamide ;
2-Amino-N- (1- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -isobutyramide;
1- (1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamino) -2-methyl-propan-2-ol; (1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -pyridin-2-yl-methylamine;
(1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -pyridin-3-ylmethyl-amine;
4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -phenol;
[2- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -phenoxy) -ethyl] -dimethyl-amine;
2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8-piperazin-1-yl-quinoline;
[2- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -ethyl] -dimethyl-amine;
2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8- (4-pyridin-2-ylmethyl-piperazin-1-yl) -quinoline;
2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8- (4-pyridin-3-ylmethyl-piperazin-1-yl) -quinoline;
2-Amino-1- (4- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -2-methyl-propane 1-one;
(S) -2-amino-1- (4- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -propan 1-one;
(S) -2-amino-1- (4- {2- [5- (2-methoxy-ethoxy) benzimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -propan-1 -one;
2-Amino-1- (4- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl} -ethanone;
(1-Amino-cyclopropyl) - (4- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -methanone;
2- (4- {2- (5- (2-Methoxy-ethoxy) benzimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) ethylamine;
(R) -2-Amino-3- (4- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -propan 1-ol;
3- {2- [5- (2-Methoxy-ethoxy) benzimidazol-1-yl] -quinolin-8-yl} -3-aza-bicyclo [3.1.0) hex-6-ylamine;
(S) -1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -pyrrolidin-3-ylamine;
(R) -1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -pyrrolidin-3-ylamine;
2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8-pyridin-3-yl-quinoline;
2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8- (6-methoxy-pyridin-3-yl) -quinoline;
4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzoic acid methyl ester;
1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -4-methyl-piperidin-4-ylamine;
1- [2- (6,7-dihydro-5,8-dioxa-1,3-diaza-cyclopenta [b] naphthalen-1-yl) -quinolin-8-yl] -piperidin-4-ylamine;
2- {1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yloxy} -ethanol;
4-cyclopropylaminomethyl-1- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ol;
1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazole-5-sulfonic acid dimethylamide;
1- [2- (6-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine;
1- [2- (5,6-Dimethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine;
2-dimethylamino-1- (4- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) ethanone;
1- [2- (5-Benzyloxy-benzimidazol-1-yl) -quinolin-8-yl] -4-methyl-piperidin-4-ol;
(4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -dimethyl-amine;
(4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -methyl-amine;
2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8- (4-morpholin-4-ylmethyl-phenyl) -quinoline;
2- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzylamino) -ethanol;
4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzylamine;
2- [5- (2-Methoxy-ethoxy} -benzoimidazol-1-yl] -8- (4-pyrrolidin-1-ylmethyl-phenyl) -quinoline;
2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8- (4-pyrrolidin-1-ylmethyl-phenyl) -quinoline;
2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8- (4-pyrrolidin-1-ylmethyl-phenyl) -quinoline;
1- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -cis-pyrrolidine-3,4-diol;
R, R- (1- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -trans-pyrrolidine-3,4-diol );
1- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -pyrrolidin-3-ol;
R- (1- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -pyrrolidin-3-ol);
S- (1- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -pyrrolidin-3-ol);
1- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -azetidin-3-ol;
2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8- [4- (4-methyl-piperazin-1-ylmethyl) -phenyl] -quinoline;
4- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -piperazine-1-carboxylic acid tert-butyl ester;
[1- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -piperidin-4-yl] -carbamic acid tert-butyl ester;
1- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -piperidin-4-ylamine;
(1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -methanol;
(1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylmethyl) -methyl-amine;
2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8- [4- (4-methyl-piperazin-1-ylmethyl) piperidin-1-yl] quinoline; (1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylmethyl) -dimethyl-amine;
1- (1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylmethyl) -pyrrolidin-3-ol;
C- (1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -methyl-amine;
1- {2- [5- (2-Dimethylamino-ethoxy) benzimidazol-1-yl] -quinolin-8-yl} -4-methyl-piperidin-4-ol;
1- {2- [5- (2-Dimethylamino-ethoxy) benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ol;
S, S- (1- (4- {2- [5- (2-Methoxy-ethoxy) benzimidazol-1-yl] -quinolin-8-yl} -benzyl) -trans-pyrrolidine-3,4-diol) ;
4- {2- [5- (3-Amino-propoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -phenol;
4- {2- [5- (3-Dimethylamino-propoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -phenol;
1- [2- (5-Phenyl-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine;
1- [2- (5-pyridin-4-yl-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine;
1- {2- [5- (3-Methoxy-phenyl) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
1- {2- (5-pyridin-3-yl-benzimidazol-1-yl) -quinolin-8-yl} -piperidin-4-ylamine;
1- {2- [5- (6-methoxy-pyridin-3-yl) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
1- {2- [5- (4-Aminomethyl-phenyl) benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
4- {1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yl} -benzoic acid methylester;
4- {1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yl} -phenol;
2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-carbonsäuremethylester;
2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-carbonsäuremethylester;
2- (5-Methoxy-benzimidazol-1-yl) -quinoline-8-carboxylic acid (2-dimethylamino-ethyl) -amide;
2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-carbonsäuremethylester;
[2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -pyrrolidin-1-yl-methanone;
[2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -morpholin-4-yl-methanone;
[2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-1-yl-methanone;
(3-Amino-pyrrolidin-1-yl) - [2- (5-cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -methanone;
8-Allyloxy-2- (5-methoxy-benzimidazol-1-yl) -quinoline;
{2- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yloxy] -ethyl} -methyl-amine;
{2- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yloxy] -ethyl} -dimethyl-amine;
2- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yloxy] -ethylamine;
1 - [[2- [5- (3-morpholinoethoxy) -1H-benzimidazol-1-yl] -quinolin-8-yl]] - piperidin-4-ylamine trihydrochloride;
1 - [[2- [5- (3-morpholinoethoxy) -1H-benzimidazol-1-yl] -quinolin-8-yl]] - piperidin-4-ylamine trihydrochloride;
5- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} - [1,3,4] oxadiazol-2-ylamine;
Ethyl-1- [8- (4-aminopiperidin-1-yl) -quinolin-2-yl] -benzimidazole-5-carboxylate;
1- [8- (4-aminopiperidin-1-yl) -quinolin-2-yl] -benzimidazole-5-carboxylic acid;
N- (4-Morpholino) ethyl-1- [8- (4-aminopiperidin-1-yl) -quinolin-2-yl] -benzimidazole-5-carboxamide;
4- {1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yl} -benzaldehyde;
1- {2- [5- (4-Methylaminomethyl-phenyl) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
1- {2- [5- (4-dimethylaminomethyl-phenyl) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
1- (2- {2- [2- (2-Methyl-imidazol-1-yl) -ethoxy] -benzimidazol-1-yl} -quinolin-8-yl) -piperidin-4-ylamine and
1- {2- [5- (2- [1,2,4] triazol-1-yl-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine,
and the pharmaceutically acceptable salts, prodrugs and solvates of the foregoing compounds.

According to the present invention, preferred compounds include those selected from the following group:
1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine;
1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-ol;
1- {2- [5- (pyridin-2-ylmethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
{1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -dimethyl-amine;
{4- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -methyl-amine;
{4- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -dimethyl-amine;
1- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine;
{1- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -dimethyl-amine;
{4- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -methyl-amine;
{4- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -dimethyl-amine;
{1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -methyl-amine;
4-dimethylaminomethyl-1- [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ol;
1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -4-methylaminomethyl-piperidin-4-ol;
4-Aminomethyl-1- [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ol;
1- {2- [5- (4-methoxy-phenyl) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
1- [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine;
1- {2- [5- (3-Dimethylamino-propoxy) benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
1- {2- [5- (3-Amino-propoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
1- {2- [5- (2-Dimethylamino-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
1- {2- [5- (pyridin-4-ylmethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
1- [2- (5-Benzyloxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine;
1- {2- [5- (pyridin-3-ylmethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
4-dimethylaminomethyl-1- [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ol;
4-Aminomethyl-1- {2- [5- (pyridin-2-ylmethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ol;
1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -dimethyl-amine;
1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -methyl-amine;
(1- {2- [5- (3-Dimethylamino-propoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -dimethyl-amine;
{1- [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -methyl-amine;
{1- [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -dimethyl-amine;
(1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -pyridin-2-ylmethyl-amine;
(1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -pyridin-3-ylmethyl-amine;
4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -phenol;
[2- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -phenoxy) -ethyl] -dimethyl-amine;
2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8-piperazin-1-yl-quinoline;
[2- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -ethyl] -dimethyl-amine;
2-Amino-1- (4- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -2-methyl-propane 1-one;
(S) -2-amino-1- (4- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -propan 1-one;
(S) -2-amino-1- (4- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -propan 1-one;
2-Amino-1- (4- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) ethanone;
2- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) ethylamine;
3- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -3-aza-bicyclo [3.1.0] hex-6-ylamine;
1- {2- [5- (2-Methoxy-ethoxy) benzimidazol-1-yl] -quinolin-8-yl} -4-methyl-piperidin-4-ylamine;
2- {1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yloxy} -ethanol;
1- [2- (5,6-Dimethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine;
1- [2- (6,7-dihydro-5,8-dioxa-1,3-diaza-cyclopenta [b] naphthalen-1-yl) -quinolin-8-yl] -piperidin-4-ylamine;
(4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -dimethyl-amine;
(4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -methyl-amine;
2- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzylamino) -ethanol;
4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl) -quinolin-8-yl} -benzylamine;
2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8- (4-pyrrolidin-1-ylmethyl-phenyl) -quinoline;
2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8- (4-pyrrolidin-1-ylmethyl-phenyl) -quinoline;
2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8- (4-pyrrolidin-1-ylmethyl-phenyl) -quinoline;
1- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -cis-pyrrolidine-3,4-diol;
R, R- (1- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -trans-pyrrolidine-3,4-diol );
1- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -pyrrolidin-3-ol;
R- (1- (4- {2- [5- (2-Methoxy-ethoxy} -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -pyrrolidin-3-ol);
S- (1- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -pyrrolidin-3-ol);
1- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -azetidin-3-ol;
2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8- [4- (4-methyl-piperazin-1-ylmethyl) -phenyl] -quinoline;
1- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -piperidin-4-ylamine;
(1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -methanol;
(1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylmethyl) -methyl-amine;
2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8- [4- (4-methyl-piperazin-1-ylmethyl) piperidin-1-yl] quinoline;
(1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylmethyl) -dimethyl-amine;
C- (1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -methyl-amine;
S, S- (1- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -trans-pyrrolidine-3,4-diol );
4- {2- [5- (3-Dimethylamino-propoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -phenol;
1- [2- (5-Phenyl-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine;
1- [2- (5-pyridin-4-yl-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine;
1- {2- [5- (3-Methoxy-phenyl) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
1- [2- (5-pyridin-3-yl-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine;
1- {2- [5- (6-methoxy-pyridin-3-yl) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
1- {2- [5- (4-Aminomethyl-phenyl) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
4- {1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yl} -benzoic acid methylester;
4- {1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yl} -phenol;
1 - [[2- [5- (3-morpholinoethoxy) -1H-benzimidazol-1-yl] -quinolin-8-yl]] - piperidin-4-ylamine trihydrochloride;
Ethyl-1- [8- (4-aminopiperidin-1-yl) -quinolin-2-yl] -benzimidazole-5-carboxylate;
N- (4-Morpholino) ethyl-1- [8- (4-aminopiperidin-1-yl) -quinolin-2-yl] -benzimidazole-5-carboxamide;
1- {2- [5- (4-Methylaminomethyl-phenyl) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
1- {2- [5- (4-dimethylaminomethyl-phenyl) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine;
1- (2- {2- [2- (2-Methyl-imidazol-1-yl) -ethoxy] -benzimidazol-1-yl} -quinolin-8-yl) -piperidin-4-ylamine and
1- {2- (5- (2- [1,2,4] triazol-1-yl-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine,
and the pharmaceutically acceptable salts, prodrugs and solvates of the foregoing compounds.

The invention further relates to a pharmaceutical composition for treating a hyperproliferative disease in a mammal comprising a therapeutically effective amount of a compound of the formula 1 or a pharmaceutically acceptable salt or prodrug, or a pharmaceutically acceptable hydrate thereof, and a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutical composition is for the treatment of cancer such as brain, lung, squamous, bladder, stomach, pancreas, breast, head, neck, renal, kidney, ovarian, prostate , colorectal, esophageal, testicular, gynecological or thyroid cancer. In a further embodiment, the pharmaceutical composition is for the treatment of a non-cancerous hyperproliferative disorder, such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).

The The invention further relates to a pharmaceutical composition for Treatment of pancreatitis or kidney disease (the proliferative Glomerulonephritis and diabetes-induced kidney disease includes) in a mammal, which is a therapeutically effective amount of a compound of the formula 1 or a pharmaceutically acceptable salt, a pharmaceutical acceptable prodrug or a pharmaceutically acceptable hydrate same and a pharmaceutically acceptable carrier.

The The invention further relates to a pharmaceutical composition for prevention a blastocytic implantation in a mammal which is a therapeutic effective amount of a compound of formula 1 or a pharmaceutically Acceptable salt, a pharmaceutically acceptable prodrug or a pharmaceutically acceptable hydrate thereof and a pharmaceutically acceptable acceptable carrier includes.

The The invention further relates to a pharmaceutical composition for Treatment of one associated with vasculogenesis or angiogenesis standing disease in a mammal, which is a therapeutically effective amount of a compound of the formula 1 or a pharmaceutically acceptable salt, a pharmaceutical acceptable prodrug or a pharmaceutically acceptable hydrate same and a pharmaceutically acceptable carrier.

In an embodiment is the pharmaceutical composition used to treat a disease, those from the group of tumor angiogenesis, a chronic inflammatory Disease, such as rheumatoid arthritis, atherosclerosis, skin diseases, like psoriasis, eczema and scleroderm, diabetes, diabetic retinopathy, Retinopathy of prematurity, age-related Macular degeneration, hemangioma, Glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreas, prostate, Colon cancer and squamous cell carcinoma is selected.

The The invention relates to a method for the treatment of a hyperproliferative Illness in a mammal, administering a therapeutically effective amount of the compound of formula 1 or a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug or a pharmaceutically acceptable Hydrate the same to the mammal. In one embodiment The method relates to the treatment of cancer, such as brain, lung, Squamous, bladder, stomach, pancreas, breast, head, Neck, esophagus, Prostate, colorectal, lung, renalem, kidney, ovary, Testicular, gynecological or thyroid cancer. In a further embodiment The method relates to the treatment of a non-cancerous hyperproliferative Disease, such as benign hyperplasia of the skin (for example, psoriasis), Restenosis or prostate (for example, benign prostatic hypertrophy (BPH)).

The The invention further relates to a method for the treatment of a hyperproliferative Illness in a mammal, administering a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug or a pharmaceutically acceptable Hydrate thereof in combination with an antitumor agent, the from the group of mitotic inhibitors, alkylating agents, antimetabolites, Intercalation antibiotics, growth factor inhibitors, cell cycle inhibitors, Enzymes, topoisomerase inhibitors, biological modifiers Response, antihormones, angiogenesis inhibitors and antiandrogens selected is, to the mammal includes.

The The invention further relates to a method for the treatment of pancreatitis or kidney disease in a mammal administering the a therapeutically effective amount of a compound of the formula 1 or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug or a pharmaceutically acceptable hydrate same to the mammal includes.

The The invention further relates to a method for the prevention of blastocytic implantation in a mammal, administering a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug or a pharmaceutically acceptable Hydrate them to the mammal includes.

The Invention further relates to a method for the treatment of diseases, associated with vasculogenesis or angiogenesis a mammal, administering a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug or a pharmaceutically acceptable Hydrate them to the mammal includes. In one embodiment The method is used to treat a disease arising from the Group of tumor angiogenesis, a chronic inflammatory Disease, such as rheumatoid arthritis, atherosclerosis, skin diseases, like psoriasis, eczema and scleroderm, diabetes, diabetic retinopathy, Retinopathy of prematurity, age-related Macular degeneration, hemangioma, Glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreas, prostate, Colon cancer and squamous cell carcinoma is selected.

patients those with compounds of formula 1 and the pharmaceutically acceptable Salts, prodrugs and hydrates of the compounds according to the methods of this invention include, for example Patients who have been diagnosed as having psoriasis, Restenosis, atherosclerosis, BPH, lung cancer, bone cancer, CMML, Pancreatic cancer, Skin cancer, cancer of the head and neck, skin or intraocular Melanoma, uterine cancer, Ovarian cancer, rectal cancer, anal cancer, stomach cancer, colon cancer, Breast cancer, testicular, gynecological Tumors (for example uterine sarcoma, fallopian tube carcinoma, endometrial carcinoma, Cervical carcinoma, Vaginocarcinoma or vulvar carcinoma), Hodgkin's disease, esophageal cancer, Small intestine cancer, Cancer of the endocrine system (for example cancer of the thyroid, parathyroid or Adrenals), soft subareas, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, solid childhood tumors, lymphocytic lymphomas, bladder cancer, Cancer of the kidney or ureter (for example, renal cell carcinoma, Carcinoma of the renal pelvis) or neoplasms of the central nervous system (for example, primary CNS lymphoma, spinal cord tumors, Brain stem gliomas or pituitary adenomas).

These The invention further relates to a pharmaceutical composition for Inhibition of abnormal cell growth in a mammal containing a lot of one Compound of formula 1 or a pharmaceutically acceptable salt or solvates or prodrugs thereof in combination with a lot a chemotherapeutic agent, wherein the amounts of the compound, of the salt, solvate or prodrug and chemotherapeutic together to inhibit abnormal cell growth. Lots Chemotherapeutics are currently known. In one embodiment is the therapeutic of the group of mitotic inhibitors, acylating agents, Antimetabolites, intercalation antibiotics, growth factor inhibitors, cell cycle inhibitors, Enzymes, topoisomerase inhibitors, biological modifiers Response, antihormones, such as antiandrogens selected.

These The invention further relates to a method for inhibiting abnormal Cell growth in a mammal or for the treatment of a hyperproliferative disorder, wherein the method of administering an amount of a compound of Formula 1 or a pharmaceutically acceptable salt or solvate or prodrugs thereof in combination with radiotherapy to the mammal wherein the amount of the compound, salt, solvate or the prodrug in combination with radiotherapy for inhibition of abnormal cell growth or treatment of hyperproliferative Disease in the mammal is effective. Techniques for administering radiotherapy are relevant known and these techniques can used in the combination therapy described here. The administration of the compound of the invention in this combination therapy can be determined as described here.

It It is believed that the compounds of formula 1 are abnormal cells for one Treatment with radiation for the purpose of killing and / or inhibiting growth make such cells more sensitive. Therefore, this concerns The invention further provides a method of sensitizing abnormal cells in a mammal for one Radiation treatment, administering a lot of one Compound of formula 1 or a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug or a pharmaceutical acceptable solvate thereof to the mammal, this amount to sensitize abnormal cells for treatment with radiation is effective. The amount of compound, salt or solvate at this procedure may be in accordance with the measures for the detection of effective amounts of such compounds, here are determined.

This invention further relates to a method and a pharmaceutical composition for inhibiting abnormal cell growth in a mammal comprising an amount of a compound of formula 1, a pharmaceutically acceptable salt or solvate thereof, a pharmaceutically acceptable prodrug thereof or an isotopically labeled derivative thereof and an amount of one or more substances selected from antiangiogenic agents, signal transduction inhibitors and antiproliferative agents are selected.

Antiangiogenic agents such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors and COX-II (cyclooxygenase II) inhibitors may be used in conjunction with a compound of formula 1 and pharmaceutical compositions described herein. Examples of useful COX-II inhibitors include CELEBREX ^™ (alecoxib), valdecoxib and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published 24 October 1996), WO 96/27583 (published 7 March 1996), European Patent Application 97304971.1 (filed 8 July 1997), European Patent Application 99308617.2 ( filed October 29, 1999), WO 98/07697 (published February 26, 1998), WO 98/03516 (published January 29, 1998), WO 98/34918 (published August 13, 1998), WO 98 / 34915 (published August 13, 1998), WO 98/33768 (published August 6, 1998), WO 98/30566 (published July 16, 1998), European Patent Publication 606,046 (published July 13, 1994), European Patent Publication 931,788 (published July 28, 1999), WO 90/05719 (published May 33, 1990), WO 99/52910 (published October 21, 1999), WO 99/52889 (published October 21, 1999) 1999), WO 99/29667 (published June 17, 1999), int PCT International Application No. PCT / IB98 / 01113 (filed July 21, 1998), European Patent Application 99302232.1 (filed March 25, 1999), UK Patent Application No. 9912961.1 (filed Jun. 3, 1999), United States Provisional Application 60/148 464 (filed 12 August 1999), U.S. Patent 5,863,949 (issued January 26, 1999), U.S. Patent 5,861,510 (issued January 19, 1999), and European Patent Publication 780 386 (published Jun. 25, 1997), all incorporated herein by reference in their entirety. Preferred MMP-2 and MMP-9 inhibitors are those which have little or no activity to inhibit MMP-1. More preferred are those containing MMP-2 and / or MMP-9 selectively over the other matrix metalloproteinases (ie MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12 and MMP-13).

Some specific examples of MMP inhibitors useful in the present invention are AG-3340, RO 32-3555, RS 13-0830, and the compounds shown in the following list:
3 - [[4- (4-fluoro-phenoxy) -benzenesulfonyl] - (1-hydroxycarbamoyl-cyclopentyl) -amino] -propionic acid;
3-exo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide;
(2R, 3R) -1- [4- (2-chloro-4-fluoro-benzyloxy) -benzenesulfonyl] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;
4- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-4-carboxylic acid hydroxyamide;
3 - [[4- (4-fluoro-phenoxy) -benzenesulfonyl] - (1-hydroxycarbamoyl-cyclobutyl) -amino] -propionic acid;
4- [4- (4-chloro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-4-carboxylic acid hydroxyamide;
(R) -3- [4- (4-chloro-phenoxy) -benzenesulfonylamino] -tetrahydropyran-3-carboxylic acid hydroxyamide;
(2R, 3R) -1- [4- (4-fluoro-2-methyl-benzyloxy) -benzenesulfonyl] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;
3 - [[4- (4-fluoro-phenoxy) -benzenesulfonyl] - (1-hydroxycarbamoyl-1-methyl-ethyl) -amino] -propionic acid;
3 - [[4- (4-fluoro-phenoxy) -benzenesulfonyl] - (4-hydroxycarbamoyl-tetrahydro-pyran-4-yl) -amino] -propionic acid;
3-exo-3- [4- (4-chloro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide;
3-endo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide; and
(R) -3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -tetrahydrofuran-3-carboxylic acid hydroxyamide;
and pharmaceutically acceptable salts and solvates of the compounds.

Other Antiangiogenic agents, the other COX-II inhibitors and others MMP inhibitors may include also be used in the present invention.

A compound of formula 1 can also be treated with signal transduction inhibitors, for example agents capable of inhibiting EGFR (epidermal growth factor receptor) reactions, for example EGFR antibodies, EGF antibodies and molecules which are EGFR inhibitors; VEGF (vascular endothelial growth factor) inhibitors such as VEGF receptors and molecules capable of inhibiting VEGF; and erbB2 receptor inhibitors, such as organic molecules or antibodies that bind to the erbB2 receptor, for example, HERCEPTIN ^™ (Genentech, Inc., South San Francisco, California, USA).

EGFR inhibitors are described, for example, in WO 95/19970 (published 27 July 1995), WO 98/14451 (published 9 April 1998), WO 98/02434 (published 22 January 1998) and US Patent 5 No. 747 498 (issued May 5, 1998) and such substances can be used in the present invention as described herein. EGFR-inhibiting agents include, but are not limited to, the monoclonal antibody C225, anti-EGFR 22Mab (ImClone Systems Incorporated, New York, New York) and ABX-EGF (Abgenix Antibody), the compounds ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX 447 (Medarex Inc, Annandale, New Jersey, USA) and OLX-103 (Merck & Co, Whitehouse Station, New Jersey, USA), VRCTC-310 (Ventech Research), and EGF Fusion Toxin (Seragen Inc. of Hopkinton, Massachusetts). , These and other EGFR-inhibiting agents can be used in the present invention.

VEGF inhibitors, for example SU-5416 and SU-6668 (Sugen Inc., South San Francisco, California, USA) also combined with the compound of the present invention become. VEGF inhibitors are published, for example, in WO 99/24440 on May 20, 1999), PCT International Application PCT / IB99 / 00797 (filed May 3, 1999), WO 95/21613 (published August 17, 1995), WO 99/61422 (published on December 2, 1999), U.S. Patent 5,834,504 (issued November 10, 1999) 1998), WO 98/50356 (published on November 12, 1998), U.S. Patent 5,883,113 (issued March 16, 1999), U.S. Patent 5,886,020 (issued March 23, 1999), U.S. Patent 5,792,783 (issued August 11, 1998), WO 99/10349 (published March 4, 1999), WO 97/32856 (published on September 12, 1997), WO 97/22596 (published Jun. 26, 1997), WO 98/54093 (published on December 3, 1998), WO 98/02348 (published January 22, 1998), WO 99/16755 (published on April 8, 1999) and WO 98/02437 (published January 22, 1998), which are all incorporated herein by reference in their entirety. Further examples of some specific VEGF inhibitors used in the present invention IM862 (Cytran Inc., Kirkland, Washington, USA), IMC-1C11 Imclone Antibody, an anti-VEGF monoclonal antibody from Genentechn, Inc., South San Francisco, California; and angiozyme, a synthetic one Ribozyme of Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California). These and other VEGF inhibitors can be found in of the present invention as described herein.

ErbB2 receptor inhibitors, as GW-282974 (Glaxo Wellcome plc) and the monoclonal antibody AR-209 (Aronex Pharmaceuticals Inc., The Woodlands, Texas, USA) and 2B-1 (Chiron) can further combined with the compound of the invention, for example in WO 98/02434 (published on January 22, 1998), WO 99/35146 (published July 15, 1999), WO 99/35132 (published on July 15, 1999), WO 98/02437 (published January 22, 1998), WO 97/13760 (published on April 17, 1997), WO 95/19970 (published July 27, 1995), U.S. Patent 5,587,458 (issued December 24, 1996) and U.S. Patent 5,877,305 issued on Mar. 2 1999), all of which are hereby incorporated by reference in their entirety, specified. ErbB2 receptor inhibitors useful in the present invention are also in the United States Provisional Application 60/117 341, filed January 27, 1999, and in the United States Provisional Application 60/117 346, filed January 27, 1999, both in their entirety are incorporated by reference. The erbB2 receptor inhibitor compounds and substances included in the the aforementioned PCT applications, US patents and US Provisional applications are described, as well as other compounds and substances that inhibit the erbB2 receptor can be linked to the compound of present invention according to the present invention Invention can be used.

The Compound of the invention may also be used by other means to Treatment of abnormal cell growth or cancer, the, without being limited thereto to be means with the ability for reinforcement of anti-tumor immune responses, such as CTLA4 (cytotoxic lymphocyte antigen 4) antibody, and other means with the ability to block CTLA4; and antiproliferative agents, such as farnesyl protein transferase inhibitors and αvβ3 inhibitors, such as the αvβ3 antibody vitaxin, and αvβ5 inhibitors and the like. Specific CTLA antibodies that used in the present invention include those described in United States Provisional Application 60/113 647 (filed on Dec. 23 1998), which is incorporated by reference in its entirety, however, you can other CTLA4 antibodies used in the present invention.

The Compounds of the formula 1 and their pharmaceutically acceptable salts, Prodrugs and solvates can each independently from each other also in a palliative neoadjuvant / adjuvant therapy in alleviating the symptoms associated with the diseases listed here and the symptoms associated with abnormal cell growth are used. Such therapy may be monotherapy be or in combination with chemo and / or immunotherapy be.

The The invention further relates to a process for the preparation of a compound the formula 1.

The Expressions "abnormal cell growth" and "hyperproliferative disorder or illness " used interchangeably in this application.

Of the used herein "abnormal Cell growth ", Unless otherwise stated, cell growth independent of normal regulatory mechanisms is (for example, loss contact inhibition). This includes the abnormal growth of: (1) Tumor cells (tumors) produced by expression of a mutant tyrosine kinase or overexpression a receptor tyrosine kinase proliferate; (2) benign and malignant Cells of other proliferative diseases in which an aberrant Tyrosine kinase activation occurs; (4) all tumors caused by receptor tyrosine kinases proliferate; (5) all tumors caused by aberrant serine / threonine kinase activation proliferate; and (6) benign and malignant cells of other proliferative diseases, where aberrant serine / threonine kinase activation occurs.

Of the As used herein, "treating" means, if not otherwise stated, the cancellation, mitigation, inhibition of progression or prevention the disorder or the condition for that phrase applies, or one or more symptoms such a disease or condition. Of the as used herein, "treatment" Unless otherwise stated, the act of treating, where "treat" as in the immediate Previous is defined.

Of the Expression "Me" means methyl, "Et" means ethyl and "Ac" means acetyl.

Of the As used herein, "halogen" means if not stated otherwise, fluorine, chlorine, bromine or iodine. preferred Halogen groups are fluorine, chlorine and bromine.

Of the as used herein, if not otherwise stated, saturated monovalent hydrocarbon radicals with straight, branched or cyclic units (the condensed and bridged bicyclic and spirocyclic Units) or a combination of the above mentioned units. For an alkyl group with cyclic units must have the group at least Have 3 carbon atoms.

Of the as used herein, "cycloalkyl" if not otherwise stated, cyclic alkyl moieties wherein alkyl is as above is defined. The use of the term "cycloalkyl" is not meant to mean the term "alkyl" on non-cyclic moieties restrictive to be viewed as.

Of the as used herein includes "alkenyl" if not otherwise stated, alkyl moieties having at least one carbon / carbon double bond, wherein alkyl is as defined above and E and Z isomers of the alkenyl moiety be included.

Of the as used herein "alkynyl" if not otherwise stated, alkyl moieties having at least one carbon / carbon triple bond, wherein alkyl is as defined above.

Of the as used herein, "alkoxy" if not otherwise indicated, O-alkyl groups, wherein alkyl is as defined above is.

Of the as used herein includes "aryl" if not stated otherwise, an organic radical that tables of a flavor Hydrocarbon derived by removing a hydrogen is, such as phenyl or naphthyl.

As used herein, the term "4- to 10-membered heterocyclyl" includes, unless otherwise specified, aromatic and non-aromatic heterocyclic groups comprising one to four heteroatoms each selected from O, S, and N, each heterocyclic group being 10 atoms in their ring system, and with the proviso that the ring of the group does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups include groups with only four atoms in their ring system, however, aromatic heterocyclic groups must have at least five atoms in their ring system. The heterocyclic groups include benzo-fused ring systems. An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl, and an example of a 10-membered heterocyclic group is quinolinyl. Examples of nonaromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl, Imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl, azabicyclo [2.2.2] hexanyl, 3H-indolyl, and quinolizinyl. Examples of aromatic heterocyclic group pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, thiazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyrazinyl , Triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl. Spiro moieties are also included within the scope of this definition, which includes 1-oxa-6-aza-spiro [2.5] oct-6-yl. The foregoing groups derived from the groups listed above may be C-linked or N-linked, if possible. For example, a pyrrole-derived group may be pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Further, an imidazole-derived group may be imidazol-1-yl (N-linked) or imidazol-3-yl (C-linked). An example of a heterocyclic group in which two ring carbon atoms are substituted with oxo (= O) units is 1,1-dioxo-thiomorpholinyl.

The phrase used herein "pharmaceutically or "pharmaceutically acceptable salts", if not otherwise stated, salts of acidic or basic groups which are used in the Compounds of formula 1 may be present. The connections of the Formula 1, which are basic in nature, can be a wide variety of Form salts with various inorganic and organic acids. The acids, for the preparation of pharmaceutically acceptable acid addition salts of such basic compounds of formula 1 can be used can, those are the non-toxic acid addition salts, i. H. salts containing pharmacologically acceptable anions, such as acetate, benzenesulfonate, Benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium acetate, Camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, Edetate, edisylate, estolate, esylate, ethylsuccinate, fumarate, Gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, Hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, Lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, Mucate, napsylate, nitrate, oleate, oxalate, pamoate (embronate), Palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, Salicylate, stearate, subacetate, succinate, tannate, tartrate, Teoclate, tosylate, triethiodide and valerate salts. There one single compound of the present invention more than one acidic or basic moiety, the compounds of the present Invention mono-, di- or trisalts in a single compound include.

The Compounds of the present invention that are acidic in nature, can Base salts with various pharmacologically acceptable cations form. examples for Such salts include the alkali metal or alkaline earth metal salts and especially the calcium, magnesium, sodium and potassium salts the compounds of the present invention.

In the compounds of formula 1, wherein terms such as (CR ⁴ R ⁵ ) _m or (CR ⁴ R ⁵ ) _t are used, R ⁴ and R ^{5 can} vary over 1 with each iteration of m or t. For example, when m or t is 2, the terms (CR ⁴ R ⁵ ) _m or (CR ⁴ R ⁵ ) _{t may be} equal to -CH ₂ CH ₂ - or -CH (CH ₃ ) C (CH ₂ CH ₃ ) (CH ₂ CH ₂ CH ₃ ) - or a number of similar moieties falling within the scope of the definitions of R ⁴ and R ⁵ .

Various Compounds of formula 1 can have asymmetric centers and therefore in different enantiomeric forms exist. All optical isomers and stereoisomers of the compounds of Formula 1 and mixtures thereof are considered to be within the scope considered the invention lying. In terms of connections of formula 1, the invention comprises the use of a racemate, one or more enantiomeric forms, one or more Enantiomeric forms, one or more diastereomeric forms or Mixtures thereof. The compounds of formula 1 can also exist as tautomers. This invention relates to the use all such tautomers and mixtures thereof.

The present invention also encompasses isotopically-labeled compounds identical to those given in Formula 1, except that one or more atoms are different from an atom having an atomic mass or mass number different from the atomic mass or mass number conventionally found in nature , are replaced. Examples of isotopes which can be incorporated in compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl, respectively. Compounds of the present invention, prodrugs thereof and pharmaceutically acceptable salts of the compounds or prodrugs containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes such as ³ H and ¹⁴ C, are useful in drug and / or substrate tissue distribution assays. Tritiated, ie, ³ H and carbon-1, ie, ¹⁴ C, isotopes are particularly preferred for their ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium, ie ² H, may have certain therapeutic benefits due to greater metabolism stability, for example increased in vivo half-life or lower dose requirements offer, and therefore be preferred in some cases. Generally, isotopically labeled compounds of Formula 1 of the present invention and prodrugs thereof may be prepared by subjecting the methods disclosed in the following Reaction Schemes and / or Examples and Preparations to replacement of a non-isotopically labeled reagent with an readily available isotopically labeled reagent.

These The invention further encompasses pharmaceutical compositions which Prodrugs of compounds of formula 1 contained th, and method for the treatment of proliferative diseases or abnormal cell growth by administration of prodrugs of compounds of formula 1. Compounds of formula 1 with free amino, amido, hydroxy or Carboxyl groups can be converted into prodrugs. Prodrugs include compounds, wherein an amino acid residue or a polypeptide chain of two or more (e.g. two, three or four) amino acid residues by an amide or ester bond covalently attached to a free amino, Hydroxy or carboxylic acid group is bound by compounds of formula 1. The amino acid residues include, but are not limited to to be, the 20 of course occurring amino acids, the usual are denoted by three-letter symbols and further include 4-hydroxyproline, hydroxylsine, demosine, isodemosin, 3-methylhistidine, Norvaline, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, Homoserine, ornithine and methionine sulfone. Other types of prodrugs are also included. For example, free carboxyl groups be derivatized as amides or alkyl esters. Free hydroxy groups can be derivatized using groups derived therefrom limited hemisuccinates, phosphate esters, dimethylaminoacetates and Phosphoryloxymethyloycarbonyls as described in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groups are also included, as well as carbonate prodrugs, Sulfonate esters and sulfate esters of hydroxy groups. The derivatization of hydroxy groups as (acyloxy) methyl and (acyloxy) ethyl ether, wherein the acyl group may be an alkyl ester optionally with Substituted groups which include, but are not limited to, ether, Include amine and carboxylic acid functionalities, or wherein the acyl group is an amino acid ester as described above is also included. Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10. Free amines can also be called amides, sulfonamides or phosphonamides be derivatized. All these product units can Include, but are not limited to, ether, amine and carboxylic acid functionalities.

Reaction Scheme 1

Reaction Scheme 1A

Reaction Scheme 1B

Reaction scheme 2

Reaction scheme 3

• W

  = Aryl or heterocycle

  X

  = C or N

Reaction scheme 4

Reaction scheme 5

• Y

  = Cl or Br

Reaction scheme 6

Reaction scheme 7

Reaction scheme 8

detailed Description of the invention

General Synthetic processes used to prepare the compounds of the present invention Invention can be used U.S. Patent 5,990,146 (issued November 23, 1999) (Warner-Lambert Co.) and the published PCT application WO 99/16755 (published on April 8, 1999) (Merck & Co.) specified. The said patent and said patent application are included here in their entirety as a reference.

The Scheme 1 explains the synthesis of compounds of formula 1. In step 1, the diol of the formula 2 with a trialkylsilyl chloride or trialkylsilyl trifluoromethanesulfonate (such as tert-butyldimethylsilyl) with a suitable organic base, such as imidazole or pyridine, in an organic solvent, such as dichloromethane (DCM), at a temperature in the range of -78 ° C to 45 ° C, preferably reacted at ambient temperature, 1 to 12 h, the compound of Formula 3 is obtained. In stage 2, a compound of Formula 3 with a triflating reagent and a base such as N-phenyl-bis- (trifluoromethanesulfonimide) and sodium hydride or trifluoromethanesulfonic anhydride and 2,6-dimethylpyridine, in an anhydrous organic solvent such as tetrahydrofuran (THF) or DCM, at a temperature in the range of -78 ° C to ambient temperature, preferably reacted at ambient temperature, 1 to 12 h, wherein the compound of formula 4 is obtained.

In Step 3 becomes a compound of formula 4 with the amine of formula 5, preferably X = C, with a palladium catalyst, for example Tris (dibenzylideneacetone) dipalladium (0) or palladium (II) acetate, and a base, such as cesium carbonate or sodium tert-butoxide, preferably cesium carbonate, and a palladium ligand, such as 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP) or 1,2-bis (diphenylphosphino) ethane (DIPHOS), in a solvent, such as 1,4-dioxane or Toluene, preferably toluene, at a temperature in the range of Ambient temperature to between 80 and 105 ° C, preferably at 105 ° C, 1 to 48 h implemented. In step 4, the compound formed is of the formula 6 under palladium catalysis using either 10% palladium on carbon or 20% palladium hydroxide on carbon, with a source of hydrogen, such as Hydrazine, ammonium formate or formic acid, in an organic solvent, such as ethanol or methanol, with or without a cosolvent, like THF, at a temperature in the range of ambient temperature to reflux temperature 1 to 24 h to give a compound of formula 7 becomes.

In Step 5 is the compound of formula 7 with formamidine acetate or formic acid in an organic solvent, such as 2-methoxyethanol, 1-butanol, ethanol or formic acid, preferably Ethanol, at a temperature in the range of ambient temperature to reflux temperature, preferably under reflux, for 1 to 48 hours, whereby a compound of the formula 8 is obtained. In level 6 becomes the compound of formula 8 with a Triflatisierungsreagens and a base such as N-phenyl-bis (trifluoromethanesulfonimide) and sodium hydride or triethylamine, in an aqueous organic solvents, such as THF, with or without a cosolvent, such as dimethylformamide (DMF) at a temperature in the range of -78 ° C to ambient, preferably reacted at ambient temperature, 1 to 24 h, using a compound of formula 9 is obtained.

In step 7, for R ¹ groups comprising an aryl or heteroaryl group (where Ar = aryl or heteroaryl), a compound of formula 9 is prepared under palladium catalysis, for example with tetrakis (triphenylphosphine) palladium (0), with the appropriate organoborane ( wherein Z = B (OH) ₂ or B (alkyl) ₂ ), organostannane (wherein Z = Sn (alkyl) ₃ ) or organozinc (wherein Z = Zn (halogen)). When Z = B (OH) ₂ , a base such as potassium phosphate in a solvent such as 1,4-dioxane or 1,2-dimethoxyethane is heated at a temperature ranging from ambient to reflux, preferably under reflux, for 1 to 48 h, whereby a compound of formula 1 is obtained. When Z = B (alkyl) ₂ , a base such as sodium carbonate, with or without lithium chloride, in a solvent system comprising ethanol and water with or without toluene, at a temperature in the range of ambient to reflux temperature, preferably around 90 ° C, 1 to 48 hours to give a compound of formula 1 is obtained. When Z = Sn (alkyl) ₃ , a reaction is carried out with or without a base, such as potassium phosphate, in a suitable organic solvent, such as toluene or 1,4-dioxane, and at a temperature ranging from ambient to reflux, preferably between 80-100 ° C for 1 to 48 hours to obtain a compound of formula 1. When Z = Zn (halogen), a suitable organic solvent, such as THF, 1,4-dioxane or 1,2-dimethoxyethane, is at a temperature in the range of -78 ° C to reflux temperature, preferably between 20 and 45 ° C, for 1 to 48 hours to give a compound of formula 1. For R ¹ having an NR ⁵ R ⁶ unit, a compound of formula 9 is reacted with an amine HNR ⁵ R ⁶ using a palladium catalyst such as tris (dibenzylideneacetone) dipalladium (0) or palladium acetate, and a base such as cesium carbonate or sodium hydroxide. tert-butoxide, preferably cesium carbonate, and a palladium ligand, such as 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP) or 1,2-bis (diphenylphosphino) ethane (DIPHOS), in a solvent, such as 1,4-dioxane, toluene and xylenes, preferably toluene, at a temperature ranging from ambient to reflux, preferably refluxing, for from 1 to 48 hours to yield a compound of formula 1. Compounds of formula 1 may have protecting groups, such as R ¹¹ , R ¹⁰ or R ⁹ = OMe, which may be removed by standard conditions as discussed in Protective Groups for Organic Synthesis. For example, R ¹¹ , R ¹⁰ or R ⁹ = OMe in R ¹¹ , R ¹⁰ or R ⁹ = OH by treatment with boron tribromide in an organic solvent such as DCM at a temperature in the range of -78 ° C to 45 ° C , preferably at ambient temperature, for 1 to 24 hours.

The Reaction scheme 1A explained an alternative synthesis of compounds of formula 7. In step 1 is the diol of formula 2 with benzyl chloride or benzyl bromide, preferably benzyl bromide, with a suitable base such as potassium carbonate, Sodium carbonate, or cesium carbonate, in an organic solvent, such as DMF at a temperature in the range of -78 ° C to 100 ° C, preferably between 60 and 80 ° C, Reacted for 3 to 24 hours to obtain a compound of the formula 3A becomes. In step 2, a compound of formula 3A is reacted with a triflation reagent and a base such as N-phenyl-bis- (trifluoromethanesulfonimide) and sodium hydride or trifluoromethanesulfonic anhydride and 2,6-dimethylpyridine, in an anhydrous organic solvent such as tetrahydrofuran (THF) or DCM, at a temperature in the range of -78 ° C to ambient temperature, preferably reacted at ambient temperature, 1 to 12 h, wherein a compound of the formula 4A (wherein V = OTf) is obtained. alternative is a compound of formula 3A with a chlorinating reagent, such as phosphorus oxychloride, thionyl chloride or oxalyl chloride, in one organic solvents, such as DCM, 1,2-dichloroethane (DCE) or chloroform, at one temperature in the range of ambient temperature to reflux temperature, preferably under refluxing, reacting with a compound of the formula 4A (where V = Cl). Alternatively, a compound of Formula 3A with a Bromierungsreagens, such as phosphorus oxybromide, in an organic solvent, such as DCM, 1,2-dichloroethane (DCE) or chloroform, at a temperature in the range of ambient temperature to reflux temperature, preferably under refluxing, reacting with a compound of the formula 4A (where V = Br).

In step 3, a compound of formula 4A is reacted with the amine of formula 5, preferably X = C, with a palladium catalyst, such as tris (dibenzylideneacetone) dipalladium (0) or palladium (II) acetate, and a base, such as cesium carbonate or sodium tert-butoxide, preferably cesium carbonate, and a palladium such as 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP) or 1,2-bis (diphenylphosphino) ethane (DIPHOS), in a solvent such as 1,4-dioxane or toluene, Preferably, toluene, at a temperature in the range of ambient temperature to 105 ° C, preferably between 80 and 105 ° C, reacted for 1 to 48 hours. In step 4, the compound of formula 6A formed is prepared by palladium catalysis using either 10% palladium on carbon, with a hydrogen source such as ammonium formate, triethylammonium formate or formic acid, preferably ammonium formate, triethylammonium formate, in an organic solvent such as ethanol (EtOH). or methanol (MeOH), with or without a cosolvent, such as THF, at a temperature ranging from ambient to reflux, preferably between 75 ° C and reflux, for 1 to 24 hours to yield a compound of Formula 7 ,

The Reaction scheme 1B explained an alternative synthesis of compounds of formula 6A. In stage 1 is the aminoquinoline of formula 2B with benzyl chloride or benzyl bromide, preferably benzyl bromide, with a suitable base such as sodium hydride or potassium hydride, in an organic solvent such as DMF, THF or 1,2-dimethoxyethane, at a temperature in the range of -78 ° C to 65 ° C, preferably between 0 and 25 ° C, 1 to 24 h reacted to give a compound of formula 3B becomes. In step 2, the compound of formula 3 with an aromatic Bromine compound of the formula 5A with a palladium catalyst, such as Tris (dibenzylideneacetone) dipalladium (0) or palladium (II) acetate, preferably tris (dibenzylideneacetone) dipalladium (0), and a base, like cesium carbonate or sodium tert-butoxide, preferably sodium tert-butoxide, and a palladium ligand such as 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP) or 1,2-bis (diphenylphosphino) ethane (DIPHOS), preferably 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP), in a solvent, such as 1,4-dioxane or toluene, at a temperature in the range of Ambient temperature up to 105 ° C, preferably between 80 and 105 ° C, Reacted for 1 to 48 hours to give a compound of formula 6A becomes.

Scheme 2 illustrates the synthesis of compounds of Formula 11. In Step 1, a compound of Formula 10 will be under standard alkylation conditions by treatment with an electrophile R ³ Y wherein Y is mesylate, tosylate, bromine, iodine, and chlorine, preferably bromine or iodine and a base such as sodium hydride, potassium hydride, sodium carbonate, potassium carbonate or cesium carbonate, preferably cesium carbonate, in an organic solvent such as DMF or THF, preferably DMF, for 1 to 48 hours at a temperature in the range of -78 ° C to 85 ° C implemented. Compounds of the type of formula 1 may also be obtained starting from the appropriate amine compound of formula 5 in step 3 of Scheme 1 or step 2 of Scheme 1A. Alternatively, compounds of the type of formula 1 may also be obtained starting from the appropriate aromatic bromine compound of formula 5A in step 2 of Scheme 1B.

Scheme 2 further illustrates the synthesis of compounds of Formula 13 (wherein Ar is an aryl or heteroaryl group). In step 2, a compound of formula 10 is reacted with a triflation reagent and a base such as N-phenyl-bis- (trifluoromethanesulfonimide) and sodium hydride or trifluoromethanesulfonic anhydride and pyridine in an anhydrous organic solvent such as THF with or without a cosolvent such as DMF, at a temperature in the range of -78 ° C to ambient temperature, preferably at ambient temperature, reacted for 1 to 24 hours, whereby a compound of formula 12 is obtained. In step 2 is a compound of formula 12 under palladium catalysis, example, with tetrakis (triphenylphosphine) palladium (0), with the appropriate organoborane (wherein Z = B (OH) ₂ or B (alkyl) ₂ ), organostannane (wherein Z = Sn (alkyl) ₃ ) or organozinc (where Z = Zn (halogen)) reacted. When Z = B (OH) ₂ , a base such as potassium phosphate in a solvent such as 1,4-dioxane or 1,2-dimethoxyethane is heated at a temperature ranging from ambient to reflux, preferably under reflux, for 1 to 48 h, whereby a compound of formula 13 is obtained. When Z = B (alkyl) ₂ , a base such as sodium carbonate with or without lithium chloride in a solvent system comprising ethanol and water with or without toluene, at a temperature in the range of ambient temperature to reflux temperature, preferably at 90 ° C, 1 used to 48 h, whereby a compound of formula 1 is obtained. When Z = Sn (alkyl) ₃ , a reaction is carried out with or without a base, such as potassium phosphate, in a suitable organic solvent, such as toluene or 1,4-dioxane, and at a temperature ranging from ambient to reflux, preferably between 80-100 ° C, for 1 to 48 hours, whereby a compound of formula 1 is obtained. When Z = Zn (halogen), a suitable organic solvent, such as THF, 1,4-dioxane or 1,2-dimethoxyethane, is at a temperature in the range of -78 ° C to reflux temperature, preferably between 20 and 45 ° C, for 1 to 48 hours to give a compound of formula 1. Compounds of formula 13 may have protecting groups, such as R ¹¹ , R ¹⁰ or R ⁹ = OMe, which may be removed by standard conditions as discussed in Protective Groups for Organic Synthesis. For example, R ¹¹ , R ¹⁰ or R ⁹ = OMe in R ¹¹ , R ¹⁰ or R ⁹ = OH by treatment with boron tribromide in an organic solvent such as DCM at a temperature in the range of -78 ° C to 45 ° C, preferably at ambient temperature, for 1 to 24 hours. Compounds of the type of formula 13 may also be obtained starting from the appropriate amine compound of formula 5 in step 3 of Scheme 1 or step 2 of Scheme 1A. Alternatively, compounds of the type of formula 1 may also be obtained starting from the appropriate aromatic bromine compound of formula 5A in step 2 of Scheme 1B.

Scheme 3 illustrates the synthesis of compounds of Formula 15 (where W = aryl or heterocycle). In step 1, a compound of formula 14 is reacted with an amine HNR ³ R ⁴ and a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride, and acetic acid in an organic solvent such as methanol or ethanol, and with or without a cosolvent such as 1,2- Dichloroethane, reacted at a temperature in the range of 0 ° C to 80 ° C, preferably at ambient temperature for 1 to 24 hours. Compounds of Formula 15 may have protecting groups, such as R ¹¹ , R ¹⁰ or R ⁹ = OMe, which may be removed by standard conditions as discussed in Protective Groups for Organic Synthesis. For example, R ¹¹ , R ¹⁰ or R ⁹ = OMe in R ¹¹ , R ¹⁰ or R ⁹ = OH by treatment with boron tribromide in an organic solvent such as DCM at a temperature in the range of -78 ° C to 45 ° C , preferably at ambient temperature, for 1 to 24 hours. Compounds of the type of formula 15 may also be obtained starting from the appropriate ArZ or amine NR ⁵ R ⁶ in step 7 of Scheme 1.

Reaction Scheme 4 illustrates the synthesis of compounds of Formula 18. In Step 1, the compound of Formula 16 is reacted with trimethylsulfonium iodide and a base such as sodium hydride in an organic solvent such as dimethylsulfoxide (DMSO) or THF at a temperature in the range of -. 78 ° C to 65 ° C, preferably reacted at ambient temperature 1 to 24 h. The resulting compound of Formula 17 is reacted in Step 2 with an amine NR ³ R ⁴ in a solvent such as THF, methanol, ethanol, water, DMF, DMSO or a combination thereof at a temperature in the range of 0 ° C to 100 ° C C, preferably at 65 ° C, reacted in a closed tube for 1 to 48 hours, whereby a compound of formula 18 is obtained. Compounds of formula 18 may have protecting groups, such as R ¹¹ , R ¹⁰ or R ⁹ = OMe, which may be removed by standard conditions as discussed in Protective Groups for Organic Synthesis. For example, R ¹¹ , R ¹⁰ or R ⁹ = OMe in R ¹¹ , R ¹⁰ or R ⁹ = OH by treatment with boron tribromide in an organic solvent, such as DCM, at a temperature in the range of -78 ° C to 45 ° C, preferably at ambient temperature, for 1 to 24 hours. Compounds of the type of formula 18 may also be obtained starting from the appropriate amine NR ⁵ R ⁶ in step 7 of Scheme 1.

Reaction Scheme 4 also illustrates the synthesis of a compound of Formula 19. In Step 1, a compound of Formula 16 is reacted with an amine HNR ³ R ⁴ and a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride, and acetic acid in an organic solvent such as methanol, ethanol, and reacted with or without a cosolvent, such as 1,2-dichloroethane (DCE), at a temperature in the range of 0 ° C to 80 ° C, preferably at ambient temperature, for 1 to 24 hours. Compounds of formula 9 may have protecting groups, such as R ¹¹ , R ¹⁰ or R ⁹ = OMe, which may be removed by standard conditions as discussed in Protective Groups for Organic Synthesis. For example, R ¹¹ , R ¹⁰ or R ⁹ = OMe in R ¹¹ , R ¹⁰ or R ⁹ = OH by treatment with boron tribromide in an organic solvent, such as DCM, at a temperature in the range of -78 ° C to 45 ° C, preferably at ambient temperature, for 1 to 24 hours. A compound of the type of formula 19 may also be obtained starting from the appropriate amine NR ⁵ R ⁶ in step 7 of Scheme 1.

The Schemes 5 and 6 explain an alternative synthetic scheme for a compound of the formula 1. In step 1, bromoaniline 20 is treated with cinnamyl chloride in one organic solvents, such as DCM or THF, preferably DCM, in the presence of an organic Base, such as pyridine or triethylamine, preferably pyridine, at Temperature in the range of -78 ° C to 40 ° C, preferably between 0 ° C and 25 ° C, during 1 acylated to give a compound of formula 21. In step 2, the compound of formula 21 is reacted with a strong Lewis acid, such as Aluminum trichloride, in an organic solvent such as chlorobenzene, at a temperature in the range of 25 ° C to 120 ° C, preferably between 90 ° C and 120 ° C, 1 to Reacted for 24 h, whereby a compound of formula 2 is obtained. In step 3, a compound of formula 22 is reacted with a triflation reagent and a base such as N-phenyl-bis (trifluoromethanesulfonimide) and sodium hydride or trifluoromethanesulfonic anhydride and 2,6-dimethylpyridine, in an anhydrous organic solvent, such as THF or DCM, at a temperature in the range of -78 ° C to ambient, preferably at ambient temperature, reacted for 1 to 24 hours, wherein a compound of formula 23 is obtained.

In Reaction Scheme 6, a compound of Formula 23 in Step 1 is reacted with an amine of Formula 5, preferably X = C, with a palladium catalyst, such as tris (dibenzylideneacetone) dipalladium (0) or palladium (II) acetate, and a base, such as cesium carbonate or sodium tert-butoxide, preferably cesium carbonate, and a palladium ligand, such as 2,2 'Bis (diphenylphosphino) -1,1'-binaphthyl (BINAP) or 1,2-bis (diphenylphosphino) ethane (DIPHOS), in a solvent such as 1,2-dioxane or toluene, preferably toluene, at a temperature within Range of ambient temperature to 105 ° C, preferably between 80 ° C and 105 ° C, reacted for 1 to 48 hours. In step 2, the resulting compound of formula 24 is reacted with iron powder and ammonium chloride in an organic solvent, such as ethanol or methanol, with or without a cosolvent, such as water, at a temperature ranging from ambient to reflux, preferably under reflux, during 1 reduced to 24 h, whereby a compound of formula 25 is obtained.

In step 3, the compound of formula 25 is reacted with formamidine acetate or formic acid in an organic solvent such as 2-methoxyethanol, 1-butanol, ethanol or formic acid, preferably ethanol, at a temperature ranging from ambient to reflux, preferably refluxing, 1 to 48 h to give a compound of formula 26 is obtained. In step 4, for R ¹ groups comprising an aryl or heteroaryl group (where Ar = aryl or heteroaryl), a compound of formula 26 is reacted with palladium catalysis, for example with tetrakis (triphenylphosphine) palladium (0), with the appropriate organoborane ( wherein Z = B (OH) ₂ or B (alkyl) ₂ ), organostannane (wherein Z = Sn (alkyl) ₃ ) or organozinc (wherein Z = Zn (halogen)). When Z = B (OH) ₂ , a base such as potassium phosphate in a solvent such as 1,4-dioxane or 1,2-dimethoxyethane is heated at a temperature ranging from ambient to reflux, preferably under reflux, for 1 to 48 h, whereby a compound of formula 1 is obtained. When Z = B (alkyl) ₂ , a base such as sodium carbonate, with or without lithium chloride, in a solvent system comprising ethanol and water with or without toluene, at a temperature in the range of ambient to reflux temperature, preferably around 90 ° C, 1 to 48 hours to give a compound of formula 1 is obtained. When Z = Sn (alkyl) ₃ , a reaction is carried out with or without a base, such as potassium phosphate, in a suitable organic solvent, such as toluene or 1,4-dioxane, and at a temperature ranging from ambient to reflux, preferably between 80-100 ° C, for 1 to 48 hours, whereby a compound of formula 1 is obtained. When Z = Zn (halogen), a suitable organic solvent, such as THF, 1,4-dioxane or 1,2-dimethoxyethane, is at a temperature in the range of -78 ° C to reflux temperature, preferably between 20 and 45 ° C, for 1 to 48 hours to give a compound of formula 1. For R ¹ having an NR ⁵ R ⁶ unit, a compound of formula 26 is reacted with an amine HNR ⁵ R ⁶ using a palladium catalyst, such as tris (dibenzylideneacetone) dipalladium (0) or palladium acetate, and a base, such as cesium carbonate or sodium hydroxide. tert-butoxide, preferably cesium carbonate, and a palladium ligand, such as 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP) or 1,2-bis (diphenylphosphino) ethane (DIPHOS), in a solvent, such as 1,4-dioxane, toluene and xylenes, preferably toluene when Y = Br, and preferably xylenes when Y = Cl, at a temperature ranging from ambient to reflux, preferably refluxing, for from 1 to 72 hours a compound of formula 1 is obtained. Compounds of formula 1 may have protecting groups, such as R ¹¹ , R ¹⁰ or R ⁹ = OMe, which may be removed by standard conditions as discussed in Protective Groups for Organic Synthesis. For example, R ¹¹ , R ¹⁰ or R ⁹ = OMe in R ¹¹ , R ¹⁰ or R ⁹ = OH by treatment with boron tribromide in an organic solvent such as DCM at a temperature in the range of -78 ° C to 45 ° C , preferably at ambient temperature, for 1 to 24 hours.

alternative For example, a compound of formula 26 can be prepared from compounds of formula 22 in a two-step reaction sequence as outlined in Reaction Scheme 7 getting produced. In step 1, a compound of formula 22, wherein X = Cl, with either phosphorus oxychloride, thionyl chloride or Oxalyl chloride, preferably oxalyl chloride, with or without one organic solvent, such as chloroform or DCE, preferably DCE, at a temperature in the range of ambient temperature to reflux temperature, preferably under reflux, reacted for 1 to 24 h, wherein a compound of Formula 27 is obtained. When X = Br, a compound of the formula becomes 22 with phosphorus oxybromide with an organic solvent such as chloroform or DCE, preferably chloroform, at a temperature in the range of Ambient temperature to reflux temperature, preferably under reflux, 1 to 24 h vice sets, with a Compound of formula 27 is obtained. In level 2, a connection is made of formula 27, wherein X = Br or Cl, with a compound of formula 28 in an organic solvent, such as DMF or 1-methyl-2-pyrrolidinone, with one or one base, such as sodium hydride or sodium bis (trimethylsilyl) amide, at a temperature in the range of ambient to 150 ° C, preferably at 60-85 ° C, when used a base, and 150 ° C without this while Reacted for 1 to 24 hours to obtain a compound of formula 26 becomes.

In step 1 of Scheme 8, a compound of formula 8 is reacted with an electrophile RY wherein Y is a mesylate, tosylate, bromide, chloride or iodide and a base such as sodium hydride, potassium hydride, potassium carbonate, sodium carbonate or cesium carbonate, in a solvent such as DMF, THF, DMSO or 1,2-dimethoxyethane, at a temperature in the range of -78 ° C to 65 ° C to give a compound of formula 29 is obtained. Compounds of formula 29 may have protecting groups, such as R ¹¹ , R ¹⁰ or R ⁹ = OMe, which may be removed by standard conditions as discussed in Protective Groups for Organic Synthesis. For example, R ¹¹ , R ¹⁰ or R ⁹ = OMe in R ¹¹ , R ¹⁰ or R ⁹ = OH by treating with boron tribromide in an organic solvent such as DCM at a temperature in the range of -78 ° C to 45 ° C , preferably at ambient temperature, for 1 to 24 hours.

As outlined in Reaction Scheme 1 in Step 1, a compound of Formula 9 is reacted with carbon monoxide in a pressure range from atmospheric pressure to 50 psi, preferably 50 psi, in the presence of an organic base such as triethylamine under palladium catalysis such as palladium acetate with a ligand , such as 1,3-bis (diphenylphosphino) propane, in a solvent such as DMF, in the presence of methanol to give a compound of formula 30. In step, the compound of formula 30 is reacted with a preformed complex of an amine NHR ³ R ⁴ (or its hydrochloride salt) with trimethylaluminum in a solvent such as DCM or DCE in a temperature range from 0 ° C to reflux temperature to give a compound of formula 31 is obtained. Compounds of formula 31 may have protecting groups, such as R ¹¹ , R ¹⁰ or R ⁹ = OMe, which may be removed by standard conditions as discussed in Protective Groups for Organic Synthesis. For example, R ¹¹ , R ¹⁰ or R ⁹ = OMe in R ¹¹ , R ¹⁰ or R ⁹ = OH by treatment with boron tribromide in an organic solvent, such as DCM, at a temperature in the range of -78 ° C to 45 ° C, preferably at ambient temperature, for 1 to 24 hours.

The Compounds of the present invention may be asymmetric carbon atoms exhibit. Diastereomeric mixtures may be in their individual Diastereomers based on their physicochemical differences by methods known to those skilled in the art, for example chromatography or fractional crystallization. enantiomers can by conversion of the enantiomeric mixtures into a mixture of diastereomers by reaction with a suitable optically active compound (e.g. an alcohol), separating the diastereomers and conversion (e.g. Hydrolysis) of the individual diastereomers in the corresponding pure enantiomers are separated. All such isomers including the Diastereomeric mixtures and pure enantiomers are considered as part of the Considered invention.

The Compounds of formulas 1, 13, 15, 18, 19, 29, 31, the basic Are nature, can a wide variety of different salts with different inorganic and organic acids form. Although such salts are for administration to animal life must be pharmaceutically acceptable it is common favorable in practice, first the compound of formula 1, 13, 15, 18, 19, 29, 31 from the reaction mixture as a pharmaceutically unacceptable salt isolate and then simply the latter into the compound of the free base by one Treatment with an alkaline reagent back to convert and then the the latter free base in a pharmaceutically acceptable acid addition salt convert. The acid addition salts the base compounds of this invention are prepared by treating the Base compound having a substantially equivalent amount of the selected mineral or organic acid in an aqueous Solvent medium or in a suitable organic solvent, such as methanol or Ethanol, produced. With careful evaporation of the solvent will be the desired one solid salt readily obtained. The desired acid salt can also be from a solution the free base in an organic solvent by adding a appropriate mineral or organic acid are precipitated to the solution.

The compounds of formula 1, 13, 15, 18, 19, 29, 31, which are acidic in nature, can form base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts, and especially sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which can be used as reagents for the preparation of the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula 1, 13, 15, 18, 19, 29, 31. Such non-toxic base salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium and magnesium, and the like. These salts can be readily prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing together lower alkanol solutions of the acidic compounds and the desired alkali metal alkoxide and then evaporating the resulting solution to dryness in the same manner as before. In any event, stoichiometric amounts of reagents are preferably used to ensure completeness of the reaction and maximum yields of the desired end product. Since a single Ver In the practice of the present invention, the compound of the present invention may comprise mono-, di- or trisalts in a single compound.

The activity the compounds of the formula 1, 13, 15, 18, 19, 29, 31 can by the following procedure can be found.

General PGT Kinase ELISA Method

• Phosphorylierungspuffer (PB): 50 mM HEPES, pH-Wert 7,3, 125 mM NaCl, 24 mM MgCl₂;
• Waschpuffer (WB): dPBS + 0,1 % Tween 20 (Polyoxyethylensorbitan); und
• Blockierungspuffer: 3 % BSA, 0,05 % Tween 20 in dPBS.

The following reagent and stock solutions are used: Adenosine triphosphate (ATP) Sigma, catalog no. A-2383 Bovine serum albumin (BSA) Sigma, catalog no. A-3294 Dulbecco's PBS (dPBS) Gibco-BRL, catalog no. 14190-136 MaxiSorp plates Nunc, catalog no. 439454 MgCl ₂ Sigma, catalog no. M-1028 Poly-Glu-Tyr (PGT) Sigma, catalog no. P-0275 TBM Micowell substrate Kirkegaard & Perry, cat. No. 50-76-05 Tween 20 Sigma, catalog no. P-1379 HRP-PY54 antibody OSI Pharmaceuticals, Inc.

• Phosphorylation buffer (PB): 50 mM HEPES, pH 7.3, 125 mM NaCl, 24 mM MgCl ₂ ;
• Wash Buffer (WB): dPBS + 0.1% Tween 20 (polyoxyethylene sorbitan); and
• Blocking buffer: 3% BSA, 0.05% Tween 20 in dPBS.

Test methods:

• (a) For plate coating, fill the Nunc MaxiSorp plate with 100 μl per well of poly-Glu-Tyr (PGT) diluted in dPBS (various concentrations). The plate is then over Night at 37 ° C incubated. The PGT supernatant is then discarded and the plates are washed three times with wash buffer washed.
• (b) The PDGF enzyme then becomes an appropriate concentration in PB dilute and 25 μl this stock solution are added per well.
• (c) ATP then becomes (from a 20 mM stock solution) to an appropriate concentration (0.5 nM-2 μM) with PB diluted. The phosphorylation reaction is added by adding 25 μl of ATP solution each well of the test plate started. The incubation will be about Shake for 10 minutes continued at room temperature.
• (d) The reaction is stopped by aspirating the reaction mixture. The plate is then washed four times with WB.
• (e) The HRP-PY54 antibody is diluted in blocking buffer to an appropriate concentration. 50 μl of this solution are then added per well followed by incubation for 25-35 min at room temperature follows. The antibody-containing solution is aspirated and the plate is again washed four times with WB.
• (f) The extent of the reaction is determined by measuring the light absorbance at 450 nm. First, color is developed by adding a TMB solution, 50 μl per well, and the reaction is allowed to proceed until wells of positive signals reach about 0.6-1.2 OD ₄₅₀ units. The color development is then stopped by adding 50 μl of 0.09 M H ₂ SO ₄ per well. The background controls are pits without PGT, but incorporated with all other components. As indicated above, a preferred signal is generally in the range of 0.6-1.2 OD units with essentially no background.

The in-vitro activity the compounds of the present invention for inhibiting PDGFβ receptor can be determined by the following procedure.

The inhibition of tyrosine kinase activity can be determined by using a recombinant enzyme in a test that demonstrates the ability of compounds to inhibit the phosphorylation of the exogenous substrate PolyGluTyr (PGT, Sigma ^™ , 4: 1). The cytoplasmic domain of the human PDGFβ receptor (amino acids 559-1106) (F. Ishikawa, et al., Nature 338: 557-562, 1989) is expressed in Sf9 insect cells as a glutathione-S-transferase (GST) fusion protein using the Baculovirus expression system expressed. The protein is then purified from the lysates of these cells using glutathione-agarose affinity columns.

The enzyme assay is performed in 96-well plates coated with the PGT substrate (0.625 μl of PGT per well). Test compounds are diluted in dimethyl sulfoxide (DMSO) and then added to the PGT plates such that the final concentration of DMSO in the assay is 1.6% (v / v). The recombinant enzyme is diluted in phosphorylation buffer (50 mM HEPES, pH 7.3, 125 mM NaCl, 24 mM MgCl ₂ ). The reaction is started by adding ATP to a final concentration of 10 μM. After 10 min incubation at room temperature with shaking, the reaction mixture is filtered off with suction and the plates are washed with washing buffer (PBS-containing 0.1% Tween 20). The amount of phosphorylated PGT is determined by incubation with horseradish peroxidase (HRP) conjugated PY-54 antibody (Transduction Labs), development with TMB peroxidase (TMB is 3,3 ', 5,5'-tetramethylbenzidine) and detection on one BioRad ^™ Microplate reading device quantified at 450 nm. The inhibition of enzymatic kinase activity by the test compound is detected as reduced absorbance, and the concentration of the compound required to inhibit the signal by 50% (under the conditions of the assay) is reported as the IC ₅₀ value for the test compound.

To determine the ability of the compounds to inhibit PDGFRβ tyrosine kinase activity for the full-length protein that exists in a cellular context, porcine aortic endothelial cells (PAE cells) transfected with the human PDGFRβ (Westermark, Bengt, et al. PNAS 87, pp. 128-132, 1990). Cells are plated and allowed to attach to 96-well dishes in the same medium (Ham's F12) with 10% FBS (fetal bovine serum) for 6-8 hours. The cells are washed, re-fed with serum-depleted medium and incubated overnight. Immediately prior to dosing a compound, the cells are re-supplied with the serum-depleted medium. Test compounds dissolved in DMSO are diluted in the medium (final DMSO concentration 0.5 (v / v)). At the end of an incubation of 10 min, PDGF-BB (final concentration 100 ng / ml) is added to the medium for an incubation of 8 min. The cells are washed with Hepes buffered saline (HBSS) and suspended in 50 μl HNTG buffer (20 mM Hepes, pH 7.5, 150 mM NaCl, 0.2% Triton ^™ X-100, 10% glycerol plus 0.2 mM PMSF (phenylmethylsulfonyl fluoride), 1 μg / ml pepstatin, 1 μg / ml leupeptin, 1 μg / ml aprotonin, 2 mM sodium pyrophosphate, 2 mM sodium orthovanadate) and then washed with 50 μl HG dilution buffer (20 mM Hepes, pH 7.5, 10% glycerol, 0.2 mM PMSF (prenylmethylsulfonyl fluoride), 1 μg / ml pepstatin, 1 μg / ml leupeptin, 1 μg / ml aprotonin, 2 mM sodium pyrophosphate, 2 mM sodium orthovanadate). The extent of phosphorylation of PDGFRβ is determined using an ELISA assay. Protein A-coated 96-well plates are blocked with Superblock (Pierce) and coated with 0.5 μg of anti-PDGFRβ-P20 antibody (Santa Cruz, Cat. No. SC-339) per well.

Any unbound antibody is washed off the plates prior to adding the cell lysate. After 2 h incubation of the lysates (50 μl) at room temperature with the PDGFRβ antibody, the PDGFRβ-associated phosphotyrosine is quantitated by development with the HRP-conjugated PY-54 antibody and TMB as described above. The ability of the compounds to inhibit the PDGF-BB-stimulated autophosphorylation reaction by 50% under the conditions used with respect to PDGF-BB-stimulated controls is reported as the IC ₅₀ value for the test compound. The compounds of the present invention, including the examples given below, generally have IC ₅₀ values using the method given above, which fall within the following range: 1-1000 nM.

Test for inhibition of activity against the KDR / VEGF receptor

The in-vitro activity the compounds of the present invention for inhibiting KDR / VEGF receptor can be determined by the following procedure.

The ability of the compounds of the present invention to inhibit tyrosine kinase activity can be determined using a recombinant enzyme in a assay that determines the ability of compounds to inhibit the phosphorylation of exogenous substrate polyGluTyr (PGT, Sigma ^™ , 4: 1). The kinase domain of the human KDR / VEGF receptor (amino acids 805-1350) is expressed in Sf9 insect cells as a glutathione-S-transferase (GST) fusion protein using the baculovirus expression system. The protein is then purified from the lysates of these cells using glutathione-agarose affinity columns.

The enzyme assay is performed in 96-well plates coated with the PGT substrate (0.625 μl of PGT per well). Test compounds are diluted in dimethyl sulfoxide (DMSO) and then added to the PGT plates such that the final concentration of DMSO in the assay is 1.6% (v / v). The recombinant enzyme is digested in phosphorylation buffer (50 mM HEPES, pH 7.3, 125 mM NaCl, 24 mM MgCl ₂ ). The reaction is started by adding ATP to a final concentration of 10 μM. After 10 min incubation at room temperature with shaking, the reaction mixture is filtered off with suction and the plates are washed with washing buffer (PBS-containing 0.1% Tween 20). The amount of phosphorylated PGT is quantified by incubation with horseradish peroxidase (HRP) conjugated PY-54 antibody (Transduction Labs), development with TMB peroxidase (TMB is 3,3 ', 5,5'-tetramethylbenzidine) and the Reaction is quantified on a BioRad ^™ Microplate reader at 450 nm. The inhibition of enzymatic kinase activity by the test compound is detected as reduced absorbance, and the concentration of the compound required to inhibit the signal by 50% (under the conditions of the assay) is reported as the IC ₅₀ value for the test compound.

to Determination of the ability of the compounds for inhibiting KDR tyrosine kinase activity for the protein full length, that in a cellular Context exists the porcine aortic endothelium (PAE), which transfects with the human KDR (Waltenberger et al., J. Biol. Chem. 269: 26988, 1994). Cells are plated out and placed on 96-well dishes in the same medium (Ham's F12) with 10% FBS (fetal bovine serum) for 6-8 h. The Cells are washed, again with serum depleted medium, containing 0.1% (v / v) bovine serum albumin (BSA) and incubated for 24 h. Immediately before dosing a compound, the cells become supplied again with the serum-depleted medium (without BSA).

Test compounds dissolved in DMSO are diluted in the medium (final DMSO concentration 0.5% (v / v)). At the end of an incubation of 2 h, VEGF ₁₆₅ (final concentration 50 ng / ml) is added to the medium for an incubation of 8 min. The cells are washed and suspended in HNTG buffer (20 mM Hepes, pH 7.5, 150 mM NaCl, 0.2% Triton ^™ X-100, 10 glycerol plus 0.2 mM PMSF (phenylmethylsulfonyl fluoride), 1 μg / ml pepstatin , 1 μg / ml leupeptin, 1 μg / ml aprotonin, 2 mM sodium pyrophosphate, 2 mM sodium orthovanadate). The extent of phosphorylation of KDR is determined using an ELISA assay: The 96-well plates are coated with 1 μg of goat anti-rabbit antibody per well. Unbound antibody is washed off the plate and remaining sites are blocked with Superblock buffer (Pierce) prior to the addition of anti-flk-1C-20 antibody (0.5 μg per plate, Santa Cruz). Any unbound antibody is washed away from the plates prior to adding the cell lysate. After incubation of the lysates with the flk-1 antibody for 2 hours, the KDR-associated phosphotyrosine is quantitated by development with the HRP-conjugated PY-54 antibody and TMB as described above. The ability of the compounds to inhibit the VEGF-stimulated autophosphorylation reaction relative to VEGF-stimulated controls is reported as the IC ₅₀ value for the test compound.

The Administration of the compounds of the present invention (hereinafter the "active connection (s)") can be through any one Procedure causes the supply of the compounds to the site of action allows. These methods include oral routes, intraduodenal routes, parenteral Injection (including intravenous, subcutaneous, intramuscular, intravascular Injection or infusion), topical and rectal administration.

The Amount of the administered active compound depends on the one to be treated Subject, the severity of the disease or disorder, the rate of administration, the disposition of the connection and the judgment of the prescriber Doctor off. However, an effective dosage is in the range of about From 0.001 to about 100 mg per kg of body weight per day, preferably about 1 to about 35 mg / kg / day in single or Divided doses. For one Humans of 70 kg makes this about 0.05 to about 7 g / day, preferably from about 0.2 to about 2.5 g / day. In some cases, dosage levels may be below the lower limit of the above-mentioned range more than adequate be while in other cases even larger doses without causing more harmful Side effects can be used, such larger doses first divided into several small doses for administration throughout the day.

The active compound may be used as a single therapy or may comprise one or more other anti-tumor substances, for example, mitotic inhibitors, for example, vinblastine; Alkylating agents, for example cisplatin, carboplatin and cyclophosphamide; Antimetabolites, for example, 5-fluorouracil, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred antimetabolites disclosed in European Patent Application 239362, such as N- (5- [N- (3,4-dihydro-2-methyl-4-oxoquinazoline) 6-methyl) -N-methyl-amino] -2-thenoyl) -L-glutamic acid; Growth factor inhibitors; Cell cycle inhibitors; Intercalation antibiotics, for example adriamycin and bleomycin; Enzymes, such as inferon; and antihormones, for example antiestrogens such as Nolvadex ^™ (tamoxifen) or, for example, antiandrogens such as Casodex ^™ (4'-cyano-3- (4-fluorophenylsulfonyl) -2-hydroxy-2-methyl-3 '- (trifluoromethyl) propionanilide) , are selected. Such a common Be Treatment can be achieved by simultaneous, sequential or separate dosing of the individual components of the treatment.

The For example, a pharmaceutical composition can be used in a oral administration suitable form as a tablet, capsule, pill, Powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as a liniment or cream or for rectal administration as a suppository. The pharmaceutical Composition can be used in the single administration of more accurate dosages suitable unit dosage forms. The pharmaceutical composition can be a conventional one pharmaceutical carrier or a conventional one pharmaceutical extender and a compound according to the invention as active ingredient. additionally It may contain other medicinal or pharmaceutical agents, carriers, adjuvants and the like.

Examples for parenteral Administration forms include solutions or suspensions of active compounds in sterile aqueous Solutions, for example, aqueous Propylene glycol or dextrose solutions. Such dosage forms can, if desired, be suitably buffered.

suitable pharmaceutical carriers include inert diluents or fillers, Water and various organic solvents. The pharmaceutical Compositions can, if desired, more Ingredients, such as flavoring agents, binders, extenders and the like. Therefore, for oral administration Tablets containing various diluents, such as citric acid, together with different decay promoting Means, like starch, alginic acid and certain complex silicates, and with binders such as sucrose, Gelatin and gum acacia, included. Further are Lubricants, such as magnesium stearate, sodium lauryl sulfate and talc, often for tableting purposes Cheap. Solid compositions of a similar Kind of can also used in soft and hard filled gelatin capsules become. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs for oral administration may be desired, the active Compound therein with various sweetening or flavoring agents, colorants or dyes and, if desired, Emulsifiers or suspending agents, together with diluents, such as water, ethanol, propylene glycol, glycerin or combinations same, combined.

method for the preparation of various pharmaceutical compositions with a specific amount of an active compound are those skilled in the art known or obvious. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa, 15th Edition (1975).

The in the following examples and preparation examples illustrate and give examples of connections of the present invention and methods of making such Connections. It goes without saying that the scope of the present invention in no way by the scope of the following Examples and preparation examples is limited. In the following examples exist molecules with a single chiral center unless otherwise stated racemic mixture. The molecules with two or more chiral centers exist unless otherwise stated as a racemic mixture of diastereomers. Single enantiomers / diastereomers can be obtained by methods known in the art.

When HPLC chromatography is given in the following Preparation Examples and Examples, the general conditions used are as follows unless otherwise indicated. The column used is a ZORBAX ^™ RXC18 column (manufactured by Hewlett Packard) of 150 mm in length and 4.6 mm in inside diameter. The samples are run on a Hewlett Packard 1100 system.

One gradient solvent used is that of 100% ammonium acetate / acetic acid buffer (0.2 M) to 100% acetonitrile 10 minutes running. The system is running then continue with a wash cycle with 100% acetonitrile for 1.5 min and then 100% buffer solution while 3 min. The flow rate over this period is constant 3 ml / min. In the following examples and Preparation Examples means "Et" ethyl, "Ac" acetyl, "Me" methyl and "Bu" butyl.

Experimental examples

Example 1 Synthesis of 1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine

Example 1A

Trifluoro-methanesulfonic acid 8- (tert-butyl-dimethyl-silanyloxy) -quinolin-2-yl ester

2,8-Quinolinediol (20.0 g, 124 mmol) was suspended in 500 mL of dichloromethane (DCM) under an atmosphere of dry nitrogen (N ₂ ). To this solution was added imidazole (20.3 g, 298 mmol) followed by tert-butyldimethylsilyl chloride (20.6 g, 137 mmol) and 4-dimethylaminopyridine (1.50 g, 12.4 mmol). The reaction mixture was stirred overnight at ambient temperature, after which it was partitioned between DCM and 1% aqueous sodium bisulfate (NaHSO ₄ ). The DCM layer was obtained and washed two more times with 1% aqueous NaHSO ₄ , then with aqueous saturated sodium bicarbonate (NaHCO ₃ ) and finally with brine. The DCM layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give crude product (40 g) as a white solid. The solid was dissolved in 500 ml of anhydrous tetrahydrofuran (THF) under an atmosphere of dry N ₂ . To this solution was added N-phenyl-bis (trifluoromethanesulfonimide) (48.7 g, 136 mmol) and the solution was cooled to 0 ° C. To this solution was added slowly (3.2 g, 136 mmol) of sodium hydride (60% in oil). Upon completion of the addition, the reaction mixture was warmed to ambient temperature. An additional 1.00 g of sodium hydride (60% in oil) was added after 1 h and stirring was continued for a further 30 min. The mixture was concentrated in vacuo and taken up in DCM. Water (1.0 ml) was slowly added dropwise to quench unreacted sodium hydride and then the reaction mixture was extracted twice from 0.1 N aqueous sodium hydroxide (NaOH) and then washed with brine. The DCM layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 57 g of the crude triflate 1A as a yellow oil.

Example 1B

([8- (tert-Butyl-dimethyl-silanyloxy) -quinolin-2-yl] - (4-methoxy-2-nitro-phenyl) -amine

Trifluoro-methanesulfonic acid 8- (tert-butyl-dimethyl-silanyloxy) -quinolin-2-yl-ester 1A (9.81 g, 24.1 mmol) and 4-methoxy-2-nitroaniline (4.86 g, 28 , 9 mmol) were dissolved in 100 ml of dioxane under an atmosphere of dry N ₂ . To this solution was added (11.0 g, 33.7 mmol) cesium carbonate (Cs ₂ CO ₃ ), (900 mg, 1.45 mmol) racemic 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl ( BINAP) and tris (dibenzylideneacetone) dipalladium (0) (883 mg, 0.964 mmol) and the reaction mixture was heated to 100 ° C and reacted at this temperature for 4 h. The mixture was then cooled to ambient temperature, concentrated in vacuo, treated with DCM, filtered and concentrated in vacuo to give a red solid. The solid was eluted on flash silica gel, eluting with hexanes / DCM (3: 1) to give 7.25 g of the title compound 1B as a red solid.

Example 1C

N ¹ - [8- (tert -butyl-dimethyl-silanyloxy) -quinolin-2-yl] -4-methoxybenzene-1,2-diamine

[(8- (tert-Butyl-dimethyl-silanyloxy) -quinolin-2-yl] -4-methoxy-2-nitro-phenyl) -amine 1B (21.9 g, 51.3 mmol) was dissolved in a solution of 200 ml of ethanol (EtOH) and 70 ml of THF are dissolved under an atmosphere of dry N ₂ . To this solution was added 10% palladium on carbon (2.18 g) followed by dropwise addition of 10 ml of anhydrous hydrazine. The reaction mixture was stirred for 2 h at ambient temperature, after which it was filtered through Celite ^™ and the Celite ^™ was washed with DCM. The combined filtrates were concentrated in vacuo and the resulting residue was partitioned between DCM and aqueous saturated NaHCO ₃ . The DCM layer was then washed again with saturated NaHCO ₃ and then brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 18.3 g of a tan solid as the title compound 1C.

Example 1D

2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-ol

N ¹ - [8- (tert -butyl-dimethyl-silanyloxy) -quinolin-2-yl] -4-methoxybenzene-1,2-diamine 1C (18.3 g, 46.1 mmol) was dissolved in 40 ml 2-methoxyethanol dissolved under an atmosphere of dry N ₂ . To this solution was added formamidine acetate (5.28 g, 50.7 mmol), and the reaction mixture was heated to 125 ° C and reacted at this temperature for 1.5 hours. The solvent was removed in vacuo and the resulting solid was triturated with ethyl ether (Et ₂ O), dried under vacuum to give 13.3 g of a pink solid as the title compound 1D.

Example 1E

Trifluoro-methanesulfonic acid (2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl ester

2- (5-Methoxybenzimidazol-1-yl) quinolin-8-ol 1D (13.9 g, 47.8 mmol) was dissolved in 100 ml of anhydrous THF under an atmosphere of dry N ₂ . To this solution was added N-phenyl-bis (trifluoromethanesulfonimide) (20.3 g, 47.8 mmol) and then the solution was cooled to 0 ° C. To this solution was added slowly (1.31 g, 54.9 mmol) of sodium hydride (60% in oil). Upon completion of the addition, the reaction mixture was warmed to ambient temperature. After 30 minutes, an additional 500 mg of sodium hydride (60% in oil) and then 3.50 g of N-phenyl-bis (trifluoro-methanesulfonimide) were added and the reaction mixture was stirred for 1 h at ambient temperature. The solvent was then removed under vacuum and the residue formed was taken up in DCM. To this solution was slowly added 1.0 ml of water to decompose unreacted sodium hydride. The mixture was then partitioned between DCM and 0.1 N aqueous NaOH. The DCM layer was then washed again with 0.1 N aqueous NaOH then brine and then dried over magnesium sulfate (MgSO ₄ ), filtered and concentrated in vacuo to give 20.7 g of a pink solid as the crude title compound 1E.

Example 1F

{1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -carbamic acid tert-butyl ester

Trifluoro-methanesulfonic acid (2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl-ester 1E (15.0 g, 35.4 mmol) and piperidine-4-yl-carbamic acid tert-butyl ester (14.2 g, 70.9 mmol) were dissolved in 200 mL dioxane under an atmosphere of dry N _2. To this solution was added Cs ₂ CO ₃ (16.2 g, 49.6 mmol), racemic BINAP (1, 28 g, 2.12 mmol) and tris (dibenzylideneacetone) dipalladium (0) (1.29 g, 1.41 mmol) and the reaction mixture was heated to 100 ° C and reacted overnight at this temperature cooled to ambient temperature, filtered and concentrated in vacuo to give an orange foam The foam was chromatographed on flash silica gel eluting with a gradient from ethyl acetate (EtOAc) / DCM (1: 5) to EtOAc / DCM (7: 3) to obtain 12.3 g of the title compound 1F as a light yellow solid.

Example 1G

1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine

{1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -carbamic acid tert-butyl ester 1F (8.40 g, 17.7 mmol) in 50 ml of trifluoroacetic acid (TFA) under an atmosphere of dry N ₂ . The reaction mixture was stirred at ambient temperature for 15 minutes after which it was concentrated under vacuum to give a yellow oil. The oil was partitioned between DCM and 0.1 N aqueous NaOH. The DCM layer was washed again with 0.1 N aqueous NaOH. The DCM layer was dried over Na ₂ SO ₄ , filtered and concentrated to give 5.85 g of the title compound 1 as a yellow solid.
CI m / z 374 [M + 1]; ¹ H-NMR _(CDCl3) δ 8 66 (s, 1 H), 8.37 (d, J = 8.9 Hz, 1 H), 8.30 (d, J = 8.7 Hz, 1 H), 7.68 (d, J = 8.9Hz, 1H), 7.47 (m, 2H), 7.35 (d, J = 2.3Hz, 1H), 7.25 (m, 1H), 7.06 (dd, J = 2.5, 8.9 Hz, 1H), 3.91 (s, 3H), 3.88 (m, 2H), 2.90 (m, 3H), 2.05 (m, 2H), 1.83 (m, 2H), 1.50 (brs, 2h).

Example 2 1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-ol

1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine 1 (500 mg, 1.10 mmol) was dissolved in 10 ml of DCM under an atmosphere of dry N ₂ solved. Boron tribromide (300 μL, 3.30 mmol) was added to this solution, and the mixture was stirred at ambient temperature overnight. Then another 200 μl boron tribromide was added and the mixture was stirred for 2 h. The reaction mixture was then poured over crushed ice and the pH of the resulting solution was adjusted to 9 by careful addition of sodium carbonate (Na ₂ CO ₃ ). The slurry was filtered and the solid was washed with water and then Et ₂ O and then dried under vacuum to give the title compound 2 as a yellow solid.
CI m / z 360 [M + 1]; ¹ H-NMR (DMSO) δ 9.07 (s, 1H), 8.76 (d, J = 8.9 Hz, 1H), 8.48 (d, J = 8.9 Hz, 1H ), 8.10 (d, J = 8.9Hz, 1H), 7.56 (d, J = 7.4Hz, 1H), 7.45 (m, 1H), 7.26 ( d, J = 7.4Hz, 1H), 7.01 (d, J = 2.2Hz, 1H), 6.95 (dd, J = 2.2, 8.9Hz, 1H) , 3.72 (m, 2H), 2.76 (m, 3H), 1.88 (m, 2H), 1.65 (m, 2H).

Example 3 1- {2- [5- (Pyridin-2-ylmethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine

Example 3A

{1- [2- (5- (hydroxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -carbamic acid tert-butyl ester

1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-ol 2 (460 mg, 1.30 mmol) was dissolved in 5 ml of anhydrous DMF under an atmosphere dissolved by dry N ₂ . To this solution was added di-tert-butyl dicarbonate (279 mg, 1.30 mmol) and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was then concentrated in vacuo and partitioned between DCM and aqueous saturated NaHCO ₃ . The DCM layer was dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give a yellow solid. The solid was chromatographed on flash silica gel eluting with EtOAc to afford 273 mg of the title compound 3A as a yellow solid.

Example 3B

1- {2- [5- (pyridin-2-ylmethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -carbamic acid tert-butyl ester

{1- [2- (5- (Hydroxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -carbamic acid tert-butyl ester 3A (73 mg, 0.16 mmol) was dissolved in 1 of anhydrous DMF was dissolved under an atmosphere of dry N _2. To this solution was added (37 mg, 0.17 mmol) potassium bis (trimethyl) silylamide (95%) followed by 2-picolyl chloride (25 μl, 0.17 mmol). The reaction mixture was stirred at ambient temperature overnight, after which the reaction mixture was concentrated under vacuum and then between DCM and aqueous saturated NaHCO _{3 was} distributed. The DCM layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a yellow gel. The gel was chromatographed on flash silica gel eluting with a gradient of DCM to DCM / MeOH (98: 2) to give 55 mg of the title compound 3B.

Example 3C

1- {2- [5- (pyridin-2-ylmethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine

1- {2- [5- (Pyridin-2-ylmethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -carbamic acid tert-butyl ester 3B (55 mg, 0.094 mmol) was dissolved in 1 ml of TFA under an atmosphere of dry N ₂ and stirred for 15 min at ambient temperature. The reaction mixture was then concentrated in vacuo to give an oil, which was then partitioned between 0.1 N aqueous NaOH and DCM. The DCM layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 38.9 mg of a yellow film as the title compound 3.
CI m / z 451 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.64 (s, 1 H), 8.60 (m, 1 H), 8.42 (dd, J = 1.5, 8.9 Hz, 1 H), 8.27 (d, J = 8.9Hz, 1H), 7.64-7.72 (m, 2H), 7.57 (d, J = 7.9Hz, 1H), 7, 45 (m, 2H), 7.40 (d, J = 2.5Hz, 1H), 7.18-7.25 (m, 3H), 5.29 (s, 2H), 3 , 87 (m, 2H), 2.92 (m, 3H), 2.04 (m, 2H), 1.80 (m, 2H), 1.60 (brs, 2H).

Example 4 {1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -dimethylamine

1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine 1 (160 mg, 0.43 mmol) was dissolved in 2 ml of chloroform under an atmosphere of dry N ₂ solved. To this solution was added 50 .mu.l of 37% aqueous formaldehyde and 100 .mu.l of formic acid, and the reaction mixture was then heated to 65.degree. C. and reacted at this temperature for 4 hours. The reaction mixture was then partitioned between DCM and 0.1 N aqueous NaOH. The DCM layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give an orange solid as the title compound 4.
CI m / z 402 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.65 (s, 1 H), 8.42 (d, J = 8.9 Hz, 1 H), 8.28 (d, J = 8.7 Hz, 1 H), 7.66 (d, J = 8.9Hz, 1H), 7.45 (m, 2H), 7.33 (d, J = 2.5Hz, 1H), 7.25 (m, 1H), 7.05 (dd, J = 2.5, 8.9 Hz, 1H), 4.00 (m, 2H), 3.89 (s, 3H), 2, 80 (m, 2H), 2.38 (m, 1H), 2.37 (s, 6H), 1.99 (m, 4H).

Example 5 {4- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -methyl-amine

Example 5A

4- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzaldehyde

Trifluoro-methanesulfonic acid (2- (5-methoxybenzimidazol-1-yl) -quinolin-8-yl ester 1E (265 mg, 0.630 mmol) was dissolved in 3 ml of dioxane under an atmosphere of dry N ₂ Solution was 4-For methylbenzene boronic acid (145 mg, 0.940 mmol), potassium phosphate (267 mg, 1.26 mmol) and tetrakis (triphenylphosphine) palladium (0) (36 mg, 0.032 mmol). The reaction mixture was heated to 105 ° C and reacted overnight at this temperature. The reaction mixture was then cooled to ambient temperature, concentrated in vacuo, partitioned between DCM and saturated aqueous NaHCO ₃ . The DCM layer was then washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a yellow solid as the title compound 5A which was used without further purification.

Example 5B

{4- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -methyl-amine

4- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzaldehyde 5A (120 mg, 0.32 mmol) was dissolved in 2 ml of methanol under an atmosphere of dry N ₂ . To this solution was added 800 μl of a solution of 2.0 M methylamine in methanol, and then acetic acid (AcOH) was added dropwise until the pH of the solution became ~5. To this solution was added (42 mg, 0.64 mmol) sodium cyanoborohydride (NaCNBH ₃ ) and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then concentrated in vacuo and then partitioned between DCM and 0.1 N aqueous NaOH. The DCM layer was washed again with 0.1 N aqueous NaOH, then dried over MgSO ₄ , filtered, and concentrated in vacuo to give 220 mg of a green residue. The residue was chromatographed on flash silica gel eluting with a gradient of DCM / MeOH (5/95) to DCM / MeOH (15/85) to DCM / MeOH / NH ₄ OH (15 / 84.5 / 0.5) 50 mg of a white solid of the title compound 5 were obtained.
CI m / z 395 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.55 (s, 1 H), 8.29 (d, J = 8.9 Hz, 1 H), 7.92 (d, J = 8.9 Hz, 1 H), 7.79 (d, J = 8.1 Hz, 1H), 7.74 (m, 1H), 7.63 (m, 3H), 7.56 (m, 1H), 7.44 (d, J = 8.1 Hz, 2 H), 7.23 (d, J = 2.3 Hz, 1 H), 6.73 (dd, J = 2.3, 8.9, 1H), 3.88 (s, 2H), 3.83 (s, 3H), 2.53 (s, 3H), 2.43 (brs, 1H).

Example 6 {4- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -dimethylamine

The procedure used for Example 5 was followed, but using 2.0 M dimethylamine in methanol instead of 2.0 M methylamine in methanol in Example 5B to give the title compound 6 as a white solid.
CI m / z 409 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.56 (s, 1 H), 8.29 (d, J = 8.7 Hz, 1 H), 7.98 (d, J = 9.1 Hz, 1 H), 7.79 (d, J = 8.1 Hz, 1H), 7.76 (m, 1H), 7.63 (m, 3H), 7.56 (m, 1H), 7.45 (d, J = 7.9 Hz, 2 H), 7.25 (d, J = 2.3 Hz, 1 H), 6.74 (dd, J = 2.3, 8.9, 1H), 3.84 (s, 3H), 3.57 (s, 2H), 2.35 (s, 6H).

Example 7 Cyclopropyl {4- [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -amine

4- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzaldehyde 5A (50 mg, 0.13 mmol) was dissolved in 500 μl dichloroethane (DCE) under an atmosphere of dry N ₂ solved. To this solution was added 80 μl of AcOH, cyclopropylamine (50 μl, 0.65 mmol) and (42 mg, 0.20 mmol) sodium triacetoxyborohydride (NaHB (OAc) ₃ ). The reaction mixture was stirred for 2 h at ambient temperature, after which an additional 20 μl of cyclopropylamine and 20 mg of NaHB (OAc) _{3 were} added and the resulting mixture was stirred overnight. The reaction mixture was then partitioned between aqueous 0.1N NaOH and DCM. The DCM layer was washed again with aqueous 0.1 N NaOH and then dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 60 mg of the title compound 7 as a yellow solid.
CI m / z 421 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.58 (s, 1 H), 8.33 (d, J = 8.7 Hz, 1 H), 7.96 (d, J = 9.1 Hz, 1 H), 7.83 (d, J = 7.7Hz, 1H), 7.77 (d, J = 7.3Hz, 1H), 7.64 (m, 3H), 7.59 (m, 1H), 7.45 (d, J = 7.9Hz, 2H), 7.25 (m, 1H), 6.75 (dd, J = 2.3, 8.9, 1 H), 3.97 (s, 2H), 3.86 (s, 3H), 2.26 (m, 1H), 1.95 (brs, 1H), 0.49 (m, 4 H).

Example 8 Tert-butyl {4- [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -amine

The procedure used for Example 7 was followed, but using tert-butylamine instead of cyclopropylamine to give the title compound 8 as a yellow solid.
CI m / z 437 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.59 (s, 1 H), 8.33 (d, J = 8.9 Hz, 1 H), 7.95 (d, J = 8.9 Hz, 1 H), 7.82 (m, 1H), 7.77 (m, 1H), 7, 65 (m, 3H), 7.58 (m, 1H), 7.49 (d, J = 8.1Hz, 2H), 7.26 (d, J = 2.3Hz, 1H), 6.79 (dd, J = 2.3, 8.9, 1H), 3.86 (s, 5H), 1.24 (s, 9H).

Example 9 4- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzylamine

The procedure used for Example 5 was followed except that ammonium acetate was used instead of 2.0 M methylamine in methanol in Example 5B to give a yellow solid. The solid was chromatographed on flash silica eluting with a gradient of DCM / MeOH (5/95) to DCM / MeOH (15/85) to DCM / MeOH / NH ₄ OH (15 / 94.5 / 0.5). whereby the title compound 9 was obtained as a white solid.
CI m / z 381 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.59 (s, 1 H), 8.35 (d, J = 8.9 Hz, 1 H), 7.94 (d, J = 8.9 Hz, 1 H), 7.84 (m, 1H), 7.78 (dd, J = 1.5, 7.3 Hz, 1H), 7.66 (m, 3H), 7.60 (m, 1 H), 7.46 (d, J = 8.1 Hz, 2 H), 7.26 (d, J = 2.5 Hz, 1 H), 6.76 (dd, J = 2.5, 8.9, 1H), 4.00 (s, 2H), 3.85 (s, 3H), 1.78 (brs, 2H).

Example 10 1- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine

The procedure used for Example 1 was followed, but using 4-ethoxy-2-nitroaniline in place of 4-methoxy-2-nitroaniline in Example 1B to give the title compound 10 as a yellow solid.
CI m / z 388 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.63 (s, 1 H), 8.36 (d, J = 8.9 Hz, 1 H), 8.26 (d, J = 8.7 Hz, 1 H), 7.64 (d, J = 8.7Hz, 1H), 7.44 (m, 2H), 7.32 (d, J = 2.5Hz, 1H), 7.25 (m, 1H), 7.05 (dd, J = 2.5, 8.9 Hz, 1H), 4.10 (q, J = 7.0 Hz, 2H), 3.86 (m , 2H), 2.90 (m, 3H), 2.04 (m, 2H), 1.79 (m, 2H), 1.45 (t, J = 7.0Hz, 3H ).

Example 11 {1- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -dimethylamine

The procedure used for Example 4 was followed except that 1- [2- (5-ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine 10 was used in place of 1- [2- (5 -Methoxybenzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine 1 to give the title compound 11 as a yellow solid.
CI m / z 416 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.65 (s, 1 H), 8.39 (d, J = 8.9 Hz, 1 H), 8.28 (d, J = 8.7 Hz, 1 H), 7.66 (d, J = 8.7Hz, 1H), 7.45 (m, 2H), 7.32 (d, J = 2.5Hz, 1H), 7.24 (m, 1H), 7.05 (dd, J = 2.5, 8.9 Hz, 1H), 4.10 (q, J = 7.0 Hz, 2H), 4.00 (m , 2H), 2.80 (m, 2H), 2.40 (m, 1H), 2.38 (s, 6H), 2.00 (m, 4H), 1.46 (t , J = 7.0 Hz, 3 H).

Example 12 1- [2- (5-Trifluoromethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine

The procedure used for Example 1 was followed, but using 2-nitro-4- (trifluoromethoxy) aniline instead of 4-methoxy-2-nitroaniline in Example 1B to give the title compound 12 as a yellow solid.
CI m / z 428 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.74 (s, 1 H), 8.50 (d, J = 8.9 Hz, 1 H), 8.33 (d, J = 8.7 Hz, 1 H), 7.74 (d, J = 1.0 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.47 (m, 2H), 7.32 (m, 1H), 7.25 (m, 1H), 3.87 (m, 2H), 2.90 (m, 3H), 2.05 (m, 2H), 1.77 (m, 2H), 1.71 (brs, 2H).

Example 13 {4- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -methylamine

The procedure used for Example 5 was followed, but using 4-ethoxy-2-nitroaniline instead of 4-methoxy-2-nitroaniline in Example 1B to give the title compound 13 as a tan solid.
CI m / z 409 [M + 1]; ¹ H-NMR _(CDCl3) δ S 8.54 (s, 1 H), 8.26 (d, J = 8.7 Hz, 1 H), 7.92 (d, J = 9.1 Hz, 1 H), 7.77 (d, J = 8.1 Hz, 1 H), 7.72 (d, J = 7.1 Hz, 1 H), 7.62 (m, 3 H), 7, 54 (m, 1 H), 7.52 (d, J = 8.1 Hz, 2 H), 7.21 (d, J = 2.5 Hz, 1 H), 6.73 (dd, J = 2.5, 8.9, 1H), 4.04 (q, J = 7.0 Hz, 2H), 3.91 (s, 2H), 2.97 (brs, 1H), 2 , 55 (s, 3H), 1.41 (t, J = 7.0 Hz, 3H).

Example 14 Cycloppropyl {4- [2- (5-ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -amine

The procedure used for Example 7 was followed, but using 4-ethoxy-2-nitroaniline in place of 4-methoxy-2-nitroaniline in Example 1B to give the title compound 14 as a yellow solid.
CI m / z 435 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.57 (s, 1 H), 8.32 (d, J = 8.7 Hz, 1 H), 7.94 (d, J = 8.9 Hz, 1 H), 7,83 (m, 1H), 7.77 (m, 1H), 7.65 (m, 3H), 7.58 (m, 1H), 7.45 (d, J = 8.1Hz, 2H), 7.25 (m, 1H), 6.76 (dd, J = 2.5, 9.1, 1H), 4.06 (q, J = 7.0 Hz, 2H) , 3.97 (s, 2H), 2.28 (m, 1H), 1.93 (brs, 1H), 1.44 (t, J = 7.0Hz, 3H), 0, 48 (m, 4H).

Example 15 Tert-butyl {4- [2- (5-ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -amine

The procedure used for Example 8 was followed except that 4-ethoxy-2-nitroaniline was used instead of 4-methoxy-2-nitroaniline in Example 1B to give the title compound 15 as a yellow solid.
CI m / z 451 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.55 (s, 1 H), 8.33 (d, J = 8.7 Hz, 1 H), 7.92 (d, J = 10.1 Hz, 1 H), 7.79 (dd, J = 1.3, 8.1 Hz, 1H), 7.71 (d, J = 7.1 Hz, 1H), 7.65 (m, 3H) , 7.55 (m, 1H), 7.48 (d, J = 8.1Hz, 2H), 7.23 (d, J = 2.5Hz, 1H), 6.78 (dd , J = 2.5, 8.9, 1H), 4.06 (q, J = 7.0 Hz, 2H), 3.89 (s, 2H), 1.43 (t, J = 7.0 Hz, 3 H), 1.28 (s, 9 H).

Example 16 {4- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -dimethylamine

The procedure used for Example 6 was followed, but using 4-ethoxy-2-nitroaniline instead of 4-methoxy-2-nitroaniline in Example 1B to give the title compound 16 as a yellow solid.
CI m / z 423 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.57 (s, 1 H), 8.31 (d, J = 8.7 Hz, 1 H), 7.96 (d, J = 8.9 Hz, 1 H), 7.80 (m, 1H), 7.75 (m, 1H), 7, 64 (m, 3H), 7.56 (m, 1H), 7.42 (d, J = 7.9Hz, 2H), 7.20 (d, J = 2.4Hz, 1H), 6.73 (dd, J = 2.4, 8.9, 1H), 4.06 (q, J = 7.0 Hz, 2H), 3.55 (s, 2H), 2.31 (s, 6H), 1.41 (t, J = 7.0 Hz, 3H) ,

Example 17 1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-one

The procedure used for Example 1 was followed, but using 4-piperidone instead of tert-butyl piperidin-4-ylcarbamate in Example 1F to give the title compound 17 as a white solid.
CI m / z 373 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.67 (s, 1 H), 8.35 (m, 2 H), 7.72 (d, J = 8.9 Hz, 1 H), 7.55 ( d, J = 1.3, 8.2, 1H), 7.50 (m, 1H), 7.36 (d, J = 2.5 Hz, 1H), 7.28 (m, 1 H), 7.04 (dd, J = 2.5, 8.9 Hz, 1H), 3.90 (s, 3H), 3.71 (m, 4H), 2.79 (m, 4 H).

Example 18 1- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-one

The procedure used for Example 17 was followed, but using 4-ethoxy-2-nitroaniline instead of 4-methoxy-2-nitroaniline in Example 1B to give the title compound 18 as a white solid.
CI m / z 387 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.57 (s, 1 H), 8.30 (m, 2 H), 7.65 (d, J = 8.7 Hz, 1 H), 7.50 ( d, J = 1.3, 8.1, 1H), 7.44 (m, 1H), 7.30 (d, J = 2.3 Hz, 1H), 7.23 (m, 1 H), 6.99 (dd, J = 2.5, 8.9 Hz, 1H), 4.07 (q, J = 7.0 Hz, 2H), 3.65 (m, 4H) , 2.74 (m, 4H), 1.42 (t, J = 7.0 Hz, 3H).

Example 19 1- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ol

1- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-one 18 (140 mg, 0.36 mmol) was dissolved in 1.5 ml of methanol under an atmosphere of dissolved dry N ₂ . To this solution was added sodium borohydride (NaBH ₄ ) (14 mg, 0.36 mmol) and the solution was stirred overnight at ambient temperature. The reaction mixture was then concentrated in vacuo and partitioned between DCM and saturated aqueous NaHCO ₃ . The DCM layer was then washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a green foam. The foam was chromatographed on flash silica gel eluting with a gradient of MeOH / DCM (1/99) to MeOH / DCM (4/96) to give the title compound 19 as a yellow foam.
CI m / z 389 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.65 (s, 1 H), 8.39 (d, J = 8.9 Hz, 1 H), 8.30 (d, J = 8.7 Hz, 1 H), 7.68 (d, J = 8.9Hz, 1H), 7.47 (m, 2H), 7.33 (d, J = 2.3Hz, 1H), 7.25 (m, 1H), 7.07 (dd, J = 2.5, 8.9Hz, 1H), 4.13 (q, J = 7.0Hz, 2H), 3.97 (m , 1H), 3.75 (m, 2H), 3.10 (m, 2H), 2.10 (m, 2H), 1.96 (m, 2H), 1.46 (t , J = 7.0 Hz, 3 H).

Example 20 Cyclopropyl {1- [2- (5-ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -amine

1- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-one 18 (130 mg, 0340 mmol) was dissolved in 1.5 ml of DCE under an atmosphere of dry N ₂ solved. To this solution was added cyclopropylamine (110 μl, 1.70 mmol) and 200 μl of ACOH, and the solution was stirred for 10 minutes. To this solution was added NaHB (OAc) ₃ (107 mg, 0.50 mmol) and the solution was stirred at ambient temperature for 5 h. The reaction mixture was then partitioned between DCM and aqueous 0.1 N NaOH. The DCM layer was washed again with aqueous 0.1 N NaOH, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 150 mg of a green foam. The foam was chromatographed on flash silica gel eluting with a gradient of MeOH / DCM (2/99) to MeOH / DCM (4/96) to give the title compound 20 as a yellow solid.
CI m / z 428 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.64 (s, 1 H), 8.38 (d, J = 9.1 Hz, 1 H), 8.28 (d, J = 8.7 Hz, 1 H), 7.66 (d, J = 8.7Hz, 1H), 7.45 (m, 2H), 7.32 (d, J = 2.5Hz, 1H), 7.25 (m, 1 H), 7.07 dd, J = 2.5, 9.1 Hz, 1 H), 4.13 (q, J = 7.0 Hz, 2 H), 3.91 (m, 2H), 2.90 (m, 3H), 2.25 (m, 1H), 2.16 (m, 2H), 1.83 (m, 2H), 1.46 (t, J = 7.0 Hz, 3H), 0.43 (m, 2H), 0.42 (m, 2H).

Example 21 Tert-butyl {1- [2- (5-ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -amine

The procedure used for Example 20 was followed, but using tert-butylamine instead of cyclopropylamine to give the title compound 21 as a yellow solid.
CI m / z 444 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.65 (s, 1 H), 8.35 (d, J = 8.9 Hz, 1 H), 8.28 (d, J = 8.9 Hz, 1 H), 7.67 (d, J = 8.7Hz, 1H), 7.45 (m, 2H), 7.32 (d, J = 2.5Hz, 1H), 7.24 (m, 1H), 7.08 (dd, J = 2.5, 8.91 Hz, 1H), 4.13 (q, J = 7.0 Hz, 2H), 3.90 (m , 2H), 2.91 (m, 2H), 2.79 (m, 1H), 2.00 (m, 2H), 1.88 (m, 2H), 1.47 (t , J = 7.0 Hz, 3H), 1.17 (s, 9H).

Example 22 {1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl) -methylamine

1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-one 17 (200 mg, 0.540 mmol) was dissolved in 2 mL MeOH under an atmosphere of dry N ₂ , To this solution was added 1.34 ml of a 2.0 M solution of methylamine in methanol and AcOH was then added to pH ~5. To this solution was added 95% NaCNBH ₃ (93 mg, 0.540 mmol) and the reaction was stirred at ambient temperature for 4 h. The reaction mixture was then concentrated in vacuo and then partitioned between DCM and aqueous 0.1 N NaOH. The DCM layer was then washed again with aqueous 0.1 N NaOH, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a green foam. The foam was chromatographed on flash silica gel eluting with a gradient of MeOH / DCM (5/95) to MeOH / DCM (10/90) to MeOH / DCM / NH ₄ OH (10/89/1) to give the title compound 22 as a green solid was obtained.
CI m / z 388 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.65 (s, 1 H), 8.38 (d, J = 8.9 Hz, 1 H), 8.29 (d, J = 8.7 Hz, 1 H), 7.67 (d, J = 8.7Hz, 1H), 7.46 (m, 2H), 7.33 (d, J = 2.3Hz, 1H), 7.25 (m, 1H), 7.08 (dd, J = 2.5, 8.9Hz, 1H), 3.93 (m, 2H), 3.89 (s, 3H), 2, 90 (m, 2H), 2.62 (m, 1H), 2.51 (s, 3H), 2.14 (m, 2H), 1.82 (m, 2H), 1, 75 (brs, 1h).

Example 23 2- (5-Methoxy-benzimidazol-1-yl) -8- (1-oxa-6-aza-spiro [2.5] -oct-6-yl) -quinoline

Trimethylsulfonium iodide (326 mg, 1.60 mmol) was dissolved in 6 mL of anhydrous dimethylsulfoxide (DMSO) under an atmosphere of dry N ₂ . To this solution was added (67.7 mg, 1.7 mmol) of sodium hydride (60% in oil) and the reaction was stirred at ambient temperature for 10 min. To this solution was added a solution of 1- [2- (5-methoxybenzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-one 17 (450 mg, 1.21 mmol) in 4 mL of anhydrous DMSO and the reaction was then stirred overnight at ambient temperature. The reaction mixture was then partitioned between EtOAc and water. The EtOAc layer was washed three more times with water and then with brine. The EtOAc layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a yellow foam as the title compound 23.
CI m / z 387 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.64 (s, 1 H), 8.39 (d, J = 8.9 Hz, 1 H), 8.31 (d, J = 8.9 Hz, 1 H), 7.68 (d, J = 8.7Hz, 1H), 7.48 (m, 2H), 7.34 (d, J = 2.3Hz, 1H), 7.29 (m, 1H), 7.06 (dd, J = 2.5, 8.9 Hz, 1H), 3.90 (s, 3H), 3.68 (m, 2H), 3, 41 (m, 2H), 2.78 (s, 2H), 2.32 (m, 2H), 1.75 (m, 2H).

Example 24 4-Dimethylaminomethyl-1- [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ol

2- (5-Methoxybenzimidazol-1-yl) -8- (1-oxa-6-aza-spiro [2.5] -oct-6-yl) -quinoline 23 (250 mg, 0.647 mmol) and 2 ml of 2 , 0 M Dimethylamine in THF were suspended in 2 ml of methanol in a pressure ampoule. The ampoule was closed with a cap, heated to 65 ° C and reacted at this temperature for 2 h. The reaction mixture was concentrated in vacuo to give a yellow solid. The solid was chromatographed on flash silica gel eluting with a gradient from MeOH / DCM (10/90) to MeOH / DCM / NH ₄ OH (10/89/1) to give 160 mg of the title compound 24 as a yellow solid.
CI m / z 432 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.64 (s, 1 H), 8.39 (d, J = 8.9 Hz, 1 H), 8.29 (d, J = 8.7 Hz, 1 H), 7.66 (d, J = 8.7Hz, 1H), 7.46 (m, 2H), 7.33 (d, J = 2.5Hz, 1H), 7.30 (m, 1H), 7.01 (dd, J = 2.5, 8.9 Hz, 1H), 3.89 (s, 3H), 3.68 (m, 2H), 3, 24 (m, 2H), 2.42 (s, 8H), 2.00 (m, 2H), 1.90 (brs, 1H), 1.79 (m, 2H).

Example 25 1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -4-methylaminomethyl-piperidin-4-ol

The procedure used for Example 5 was followed, but using 2.0 M methylamine in methanol instead of 2.0 M dimethylamine in THF to give the title compound 25.
CI m / z 418 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.65 (s, 1 H), 8.32 (m, 2 H), 7.67 (d, J = 8.7 Hz, 1 H), 7.46 ( m, 2 H), 7.33 (d, J = 2.3 Hz, 1 H), 7.29 (m, 1 H), 7.02 (dd, J = 2.5, 8.9 Hz, 1 H), 3.90 (s, 3H), 3.70 (m, 2H), 3.23 (m, 2H), 2.65 (s, 2H), 2.54 (s, 3H), 2.04 (m, 2H), 1.79 (m, 2H).

Example 26 4-Aminomethyl-1- [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ol

The procedure used for Example 24 was followed except that ammonium hydroxide was used instead of 2.0 M dimethylamine in THF and the solvent was THF instead of methanol to give the title compound 26. CI m / z 404 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.65 (s, 1 H), 8.30 (m, 2 H), 7.66 (d, J = 8.9 Hz, 1 H), 7.47 ( m, 2 H), 7.33 (d, J = 2.5 Hz, 1 H), 7.29 (m, 1 H), 7.01 (dd, J = 2.3, 8.9 Hz, 1 H), 3.89 (s, 3H), 3.71 (m, 2H), 3.23 (m, 2H), 2.78 (s, 2H), 1.96 (m, 2H), 1.79 (m, 2H).

Example 27 1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -pyrrolidin-3-ylamine

The procedure used for Example 1 was followed, but using (+/-) - 3- (tert-butoxycarbonyl-amino) -pyrrolidine in place of the piperidine-4-yl-carbamic acid tert-butyl ester in Example 1F to give the title compound 27 as the title compound yellow solid was obtained.
CI m / z 360 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.61 (s, 1 H), 8.23 (d, J = 8.7 Hz, 1 H), 7.83 (d, J = 8.9 20 Hz, 1 H), 7.59 (d, J = 8.7 Hz, 1 H), 7.40 (m, 1 H), 7.33 (d, J = 2.3 Hz, 1 H), 7, 19 (d, J = 8.5 Hz, 1 H), 7.00 (dd, J = 2.5, 8.9 Hz, 1 H), 6.83 (d, J = 7.9 Hz, 1 H), 4.00 (m, 1H), 3.90 (m, 1H), 3.88 (s, 3H), 3.75 (m, 2H), 3.56 (m, 1 H), 2.24 (m, 1H), 1.92 (brs, 2H), 1.82 (m, 1H).

Example 28 1- (2-Benzimidazol-1-yl) -quinolin-8-yl) -piperidin-4-ylamine

Example 28A

Benzyloxy-quinoline-2-ylamine

2-Amino-8-hydroxyquinoline (20.0 g, 122 mmol) was dissolved in 50 mL of anhydrous DMF under an atmosphere of dry N ₂ . The reaction mixture was cooled to 0 ° C after which sodium hydride (4.89 g, 122 mmol) (60% in oil) was added slowly and the reaction mixture was stirred for 30 min.

To this solution was added benzyl bromide (14.5 mL, 122 mmol) and the reaction mixture was then warmed to ambient temperature and stirred overnight. The reaction mixture was then filtered and the resulting solid was washed with Et ₂ O and then dried under vacuum to give 29.4 g of the title compound 28A as a white solid.

Example 28B

(8-Benzyloxy-quinolin-2-yl) - (2-nitro-phenyl) -amine

Benzyloxy-quinolin-2-ylamine 28A (3.50 g, 14.0 mmol) and 1-bromo-2-nitrobenzene (3.20 g, 15.4 mol) were dissolved in 70 ml of dioxane under an atmosphere of dry N ₂ solved. To this solution was added Cs ₂ CO ₃ (18.3 g, 56.0 mmol), racemic BINAP (1.00 g, 1.68 mmol) and tris (dibenzylideneacetone) dipalladium (0) (513 mg, 0.560 mmol) , The reaction mixture was heated to 100 ° C and reacted overnight at this temperature. The mixture was then cooled to ambient temperature, concentrated in vacuo, treated with DCM, filtered and concentrated in vacuo to give a red solid. The solid was chromatographed on flash silica gel eluting with DCM to give 5.16 g of the title compound 28B as an orange solid.

Example 28C

2- (2-Amino-phenylamino) -quinolin-8-ol

(8-Benzyloxy-quinolin-2-yl) - (2-nitro-phenyl) -amine 28B (5.16 g, 13.9 mmol) was suspended in 60 mL of EtOH under an atmosphere of dry N ₂ . To this solution was added ammonium formate (17.5 g, 278 mmol) and 550 mg of 20% palladium hydroxide on carbon. The reaction mixture was heated to 78 ° C. and stirred for 2 hours at this temperature, after which it was cooled to ambient temperature and filtered through Celite ^™ . The Celite ^™ was washed with ethanol, the filtrates were combined and concentrated in vacuo to give the title compound 28C, which was then crude to the next step.

Example 28 D

1- (2-benzimidazol-1-yl-quinolin-8-yl) -piperidin-4-ylamine

The procedure used for Example 5 was followed except that the compound 2- (2-amino-phenylamino) -quinolin-8-ol 28C instead of 2- (5-methoxy-benzimidazol-1-yl) quinolin-8-ol 1D in Example 1 to give the title compound 28.
CI m / z 344 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.71 (s, 1 H), 8.43 (m, 1 H), 8.31 (d, J = 8.9 Hz, 1 H), 7.89 ( m, 1H), 7.71 (d, J = 8.7Hz, 1H), 7.36-7.49 (m, 4H), 7.24 (m, 1H), 3.89 (m, 2H), 2.90 (m, 3H), 2.04 (m, 2H), 1.82 (m, 2H), 1.28 (brs, 2H).

Example 29 1- (2-Imidazolo [4,5-b] pyridin-3-yl-quinolin-8-yl) -piperidin-4-ylamine

The procedure used for Example 28 was followed using 2-chloro-3-nitropyridine in place of 1-bromo-2-nitrobenzene in Example 28B to give the title compound 29.
CI m / z 345 [M + 1]; ¹ H-NMR _(CDCl3) δ 9.36 (s, 1 H), 9.00 (d, J = 8.9 Hz, 1 H), 8.49 (dd, J = 1.4, 4, 7 Hz, 1 H), 8.34 (d, J = 8.9 Hz, 1 H), 8.15 (dd, J = 1.4, 8.1, 1 H), 7.45 (m, 2 H), 7.33 (dd, J = 4.8, 8.1 Hz, 1 H), 7.17 (dd, J = 1.7, 7.1 1 H), 3.93 (m, 2H), 2.98 (m, 1H), 2.91 (m, 2H), 2.12 (m, 2H), 1.98 (brs, 2H), 1.88 (m, 2H).

Example 30 1- {2- [5- (4-Methoxy-phenyl) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine

Example 30A

4'-methoxy-3-nitro- biphenyl-4-ylamine

To a solution of 30 ml of water and 40 ml of dioxane was added 4-methoxyphenylboronic acid (1.69 g, 11.1 mmol), 4-bromo-2-nitroaniline (2.18 g, 10.0 mmol), tetrakis (triphenylphosphine). palladium (0) (580 mg, 0.502 mmol) and Na ₂ CO ₃ (6.00 g, 56.6 mmol) under an atmosphere of dry N ₂ . The reaction mixture was then heated to 80 ° C and stirred overnight at this temperature. The reaction mixture was then partitioned between DCM and water. The DCM layer was then washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was chromatographed on flash silica gel eluting with a gradient starting from DCM / hexanes (1: 1) to DCM to give the title compound 30A (2.38 g, 2.38 g).

Example 30B

1- {2- [5- (4-methoxy-phenyl) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine

The procedure used for Example 1 was followed except that 4'-methoxy-3-nitro-biphenyl-4-ylamine was used in place of 4-methoxy-2-nitroaniline in Example 1B to give the title compound 30.
CI m / z 450 [M + 1]; ¹ H NMR _(CDCl3) δ 8.71 (s, 1 H), 8.43 (d, J = 8.7 Hz, 1 H), 8.28 (d, J = 8.7 Hz, 1 H), 8.01 (d, J = 1.5 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.62 (m, 3H), 7.45 (m, 2H), 7.35 (dd, J = 1.3, 5.8Hz, 1H), 6.99 (dd, J = 2.1, 6.9Hz, 2H), 3 , 98 (m, 2H), 3.83 (s, 3H), 2.88 (m, 3H), 2.04 (m, 2H), 1.83 (m, 2H), 1 , 77 (brs, 2h).

Example 31 (4- {2- [5- (4-Methoxy-phenyl) -benzimidazol-1-yl] -quinolin-8-yl} -benzyl) -methylamine

The procedure used for Example 5 was followed except that the compound 4'-methoxy-3-nitro-biphenyl-4-ylamine 30A was used in place of 4-methoxy-2-nitroaniline in Example 1B to give the title compound 31.
CI m / z 471 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.60 (s, 1 H), 8.27 (d, J = 8.9 Hz, 1 H), 8.02 (d, J = 8.7 Hz, 1 H), 7.91 (d, J = 1.5 Hz, 1H), 7.76 (m, 2H), 7.64 (m, 3H), 7.47-7.57 (m, 5H), 7.31 (dd, J = 1.7, 8.5 Hz, 1H), 6.96 (m, 2H), 3.91 (s, 2H), 3.82 (s , 3H), 2.87 (brs, 1H), 2.55 (s, 3H).

Example 32 1- [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine

{1- [2- (5- (Hydroxybenzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -carbamic acid tert-butyl ester 3A (200 mg, 0.435 mmol) was dissolved in 1.5 ml of anhydrous DMF under an atmosphere of dry N ₂ . To this solution was added Cs ₂ CO ₃ (170 mg, 0.520 mmol) followed by cyclopropylmethane bromide (46 μL, 0.48 mmol). The reaction mixture was then heated to 65 ° C and stirred for 4 h at this temperature. The reaction mixture was then cooled to ambient temperature and partitioned between EtOAc and water. The EtOAc layer was washed four more times with water and then with brine. The EtOAc was then dried over Na ₂ SO ₄ , filtered and concentrated in vacuo and the resulting green oil was chromatographed on flash silica gel eluting with MeOH / DCM (2:98) to give a green oil. The oil was dissolved in 1.5 ml of TFA under an atmosphere of dry N ₂ . The reaction mixture was stirred at ambient temperature for 10 minutes, after which it was concentrated in vacuo, and the residue formed was partitioned between DCM and aqueous 0.1 N NaOH. The DCM layer was then washed with basic saline (pH = 10), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 118 mg of the title compound as a yellow solid 32.
CI m / z 414 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.63 (s, 1 H), 8.37 (d, J = 8.9 Hz, 1 H), 8.27 (d, J = 8.7 Hz, 1 H), 7.65 (d, J = 8.7Hz, 1H), 7.44 (m, 2H), 7.30 (d, J = 2.5Hz, 1H), 7.24 (m, 1H), 7.09 (dd, J = 2.5, 8.9Hz, 1H), 3.87 (m, 4H), 2.87 (m, 3H), 2, 03 (m, 2H), 1.81 (m, 2H), 1.56 (brs, 102H), 1.32 (m, 1H), 0.66 (m, 2H), 0, 39 (m, 2H).

Example 33 1- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine

The procedure used for Example 1 was followed except that trifluoromethanesulfonic acid 2- [5- (2-methoxyethoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 77E was used instead of trifluoromethanesulfonic acid (2 (5-methoxybenzimidazol-1-yl) quinolin-8-yl ester 1E was used in Example 1F, whereby the title compound 33 was obtained.
CI m / z 418 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.65 (s, 1 H), 8.40 (d, J = 8.7 Hz, 1 H), 8.29 (d, J = 8.7 Hz, 1 H), 7.67 (d, J = 8.7 Hz, 1 H), 7.45 (m, 2 H), 7.35 (d, J = 2.5 Hz, 1 H), 7, 25 (m, 1H), 7.13 (dd, J = 2.5, 8.7 Hz, 1H), 4.22 (m, 2H), 3.88 (m, 2H), 3 , 81 (m, 2H), 3.48 (s, 3H), 2.89 (m, 3H), 2.05 (m, 2H), 1.82 (m, 2H), 1 , 57 (brs, 2h).

Example 33A 1- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine p-toluenesulfonate salt

1- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine 33 (15.13 g, 36.2 mmol) was added in 93 ml of EtOH and the reaction mixture was heated to reflux temperature under an atmosphere of dry N ₂ . To this solution was added p-toluenesulfonic acid monohydrate (6.89 g, 36.2 mmol), which was then stirred overnight under refluxing. The reaction mixture was then cooled to ambient temperature and filtered. The filter cake was washed with EtOH, dried under vacuum to give 18.46 g of the title compound 33A as an off-white solid.
¹ H NMR (CD ₃ OD) δ 8.93 (s, 1 H), 8.57 (d, J = 9.1 Hz, 1 H), 8.40 (d, J = 8.7 Hz, 1 H), 7.89 (d, J = 8.7 Hz, 1 H), 7.68 (d, J = 6.2 Hz, 2 H), 7.58 (m, 1 H), 7, 49 (m, 1 H), 7.33 (dd, J = 1.2, 7.9 Hz, 1 H), 7.25 (d, J = 2.5 Hz, 1 H), 7.17 ( m, 3H), 4.18 (m, 2H), 3.93 (m, 2H), 3.77 (m, 2H), 3.43 (s, 3H), 3.30 ( m, 1H), 2.86 (m, 2H), 2.31 (s, 3H), 2.16 (m, 2H), 2.06 (m, 2H).

Example 34 1- {2- [5- (Pyridin-3-ylmethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine

The method used for Example 32 was followed except 3-picolyl chloride hydrochloride was used instead of Cyclopropylmethanbromid in Example 32 and were the equivalents of Cs ₂ CO ₃ doubled, whereby the title compound was obtained 34th
CI m / z 451 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.73 (d, J = 2.3 Hz, 1 H), 8.65 (s, 1 H), 8.58 (dd, J = 1.4, 5, 0Hz, 1H), 8.42 (d, J = 8.9Hz, 1H), 8.29 (d, J = 8.7Hz, 1H), 7.82 (m, 1H) , 7.66 (d, J = 8.7Hz, 1H), 7.46 (m, 2H), 7.41 (d, J = 2.5Hz, 1H), 7.31 (m , 1H), 7.26 (m, 1H), 7.13 (m, 1H), 5.17 (s, 2H), 3.88 (m, 2H), 2.91 (m , 3H), 2.03 (m, 2H), 1.80 (m, 2H), 1.61 (brs, 2H).

Example 35 1- [2- (5-Benzyloxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine

The procedure used for Example 32 was followed, but using benzyl bromide instead of cyclopropylmethane bromide to give the title compound 35.
CI m / z 450 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.65 (s, 1 H), 8.42 (d, J = 8.9 Hz, 1 H), 8.30 (d, J = 8.7 Hz, 1 H), 7.67 (d, J = 8.7 Hz, 1 H), 7.37-7.51 (m 7 H), 7.33 (d, J = 7.3 Hz, 1 H), 7.26 (m, 1H), 7.18 (dd, J = 2.5, 8.9 Hz, 1H), 5.16 (s, 2H), 3.88 (m, 2H) , 2.90 (m, 3H), 2.04 (m, 2H), 1.81 (m, 2H), 1.40 (brs, 2H).

Example 36 1- {2- [5- (Pyridin-4-ylmethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine

The procedure used for Example 32 was followed except that the 4-picolyl chloride hydrochloride salt was used instead of cyclopropylmethane bromide and the equivalents of Cs ₂ CO _{3 were} doubled to give the title compound 36.
CI m / z 451 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.65 (s, 1 H), 8.63 (m, 2 H), 8.44 (d, J = 9.1 Hz, 1 H), 8.31 ( d, J = 8.9Hz, 1H), 7.68 (d, J = 8.7Hz, 1H), 7.47 (m, 2H), 7.41 (d, J = 6, 0Hz, 2H), 7.37 (d, J = 2.3Hz, 1H), 7.26 (m, 1H), 7.16 (dd, J = 2.3, 9.1Hz , 1H), 5.19 (s, 2H), 3.90 (m, 2H), 2.90 (m, 3H), 2.05 (m, 2H), 1.80 (m , 2H), 1.55 (brs, 2H).

Example 37 1- {2- [5- (2-Dimethylamino-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine

The procedure used for Example 32 was followed except that the hydrochloride salt of 2-dimethylaminoethyl chloride was used instead of cyclopropylmethane bromide and the equivalents of Cs ₂ CO _{3 were} doubled to give the title compound 37.
CI m / z 431 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.61 (s, 1 H), 8.45 (d, J = 8.9 Hz, 1 H), 8.27 (d, J = 8.7 Hz, 1 H), 7.62 (d, J = 8.7 Hz, 1H), 7.44 (m, 2H), 7.31 (m, 1H), 7.24 (m, 1H), 7.12 (m, 1H), 4.12 (m, 2H), 3.72-3.88 (m, 4H), 2.90 (m, 3H), 1.78-2, 10 (m, 12H).

Example 38 1- {2- [5- (3-Amino-propoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine

Example 38A

1- (2- {5- [3- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -propoxy] -benzoimidazol-1-yl} -quinolin-8-yl) -piperidine 4-yl] -carbamic acid tert-butyl ester

the for example 32 used procedures were followed, however, using N- (3-bromopropyl) phthalimide instead of cyclopropylmethane bromide and the tert-butylcarbamate ester intermediate was none TFA-mediated cleavage to give the title compound 38A was obtained as a yellow solid.

Example 38B

(1- {2- [5- (3-Amino-propoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -carbamic acid tert-butyl ester

1- (2- {5- [3- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -propoxy] -benzoimidazol-1-yl} -quinolin-8-yl) -piperidine 4-yl] -carbamic acid tert-butyl ester 38A (200 mg, 0.31 mmol) was dissolved in 1 mL of EtOH under an atmosphere of dry N ₂ . To this solution was added 50 μl of hydrazine and the resulting solution was stirred for 3 hours at ambient temperature. The reaction mixture was then filtered, concentrated in vacuo, and purified by silica chromatography eluting with DCM / MeOH / NH ₄ OH (89/10/1) to give 120 mg of the title compound 38B as a yellow film.

Example 38C

1- {2- [5- (3-Amino-propoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine

1- {2- [5- (3-Amino-propoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -carbamic acid tert-butyl ester 38B (175 mg, 0.42 mmol) was dissolved in a solution of 0.5 ml TFA and 0.5 ml DCM under an atmosphere of dry N ₂ and stirred for 1 h at ambient temperature. The reaction mixture was then concentrated in vacuo and then partitioned between DCM and aqueous 1N NaOH. The DCM layer was then dried over MgSO ₄ , filtered and concentrated to afford the title compound 38 as a light green solid.
CI m / z 417 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.63 (s, 1 H), 8.36 (d, J = 8.7 Hz, 1 H), 8.26 (d, J = 8.7 Hz, 1 H), 7.64 (d, J = 8.7Hz, 1H), 7.44 (m, 2H), 7.31 (d, J = 2.5Hz, 1H), 7.23 (m, 1H), 7.04 (m, 1H), 4.12 (t, J = 6.2Hz, 2H), 3.87 (m, 2H), 2.89 (m, 3H), 2.03 (m, 2H), 1.94 (m, 2H), 1.77 (m, 2H), 1.54 (brs, 4H).

Example 39 1- {2- [5- (3-Dimethylamino-propoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine

1- {2- [5- (3-Amino-propoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -carbamic acid tert-butyl ester 38B (120 mg, 0.288 mmol) was dissolved in a cooled (0 ° C) solution of 1 mL of acetonitrile (ACN) and 0.5 mL of formaldehyde (37 wt .-% in water) under an atmosphere of dry N _2. To this solution was added NaCNBH ₃ (72 mg, 1.2 mmol) and the solution was stirred for 30 min, after which 200 μl of AcOH was added. The reaction mixture was then warmed to ambient temperature and stirred overnight. The reaction mixture was then concentrated in vacuo and partitioned between aqueous 0.1 N NaOH and DCM. The aqueous layer was washed three more times with DCM. The DCM extracts were combined, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a green film. The film was purified using flash silica gel chromatography eluting with DCM / MeOH / NH ₄ OH (89.9 / 10 / 0.1) to give 70 mg of the tert-butylcarbonyl protected product. This residue was dissolved in a solution of 1 ml TFA and 1 ml DCM under an atmosphere of dry N ₂ . The reaction mixture was stirred for 1 h after which it was concentrated in vacuo, partitioned between DCM and aqueous 1N NaOH. The aqueous layer was washed twice more with DCM. The DCM extracts were combined and dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a yellow film. The film was purified using flash silica gel chromatography using DCM / MeOH / NH ₄ OH (84.9 / 15 / 0.1) to give 30 mg of the title compound 39 as a yellow film.
CI m / z 445 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.87 (s, 1 H), 8.58 (d, J = 8.8 Hz, 1 H), 8.31 (dd, J = 2.0, 8, 7Hz, 1H), 7.80 (ddJ = 2.0, 8.7Hz, 1H), 7.48 (m, 1H), 7.43 (m, 1H), 7.25 (m, 1H), 7.17 (d, J = 2.1Hz, 1H), 7.10 (m, 1H), 4.02 (m, 2H), 3.78 (m, 2H), 2.71-2.84 (m, 3H), 2.53 (m, 2H), 2.27 (s, 6H), 2.03 (m, 2H), 1, 99 (m, 4H), 1.79 (m, 2H).

Example 40 Ethyl 1- [2- (5-methoxybenzimidazol-1-yl] quinolin-8-yl] piperidine-4-carboxylate

The procedure used for Example 1 was followed except that ethyl isonipecotate was used in place of the piperidine-4-yl-carbamic acid tert-butyl ester in Example 1F to give the title compound 40 as a yellow solid.
CI m / z 431 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.64 (s, 1 H), 8.40 (d, J = 8.9 Hz, 1 H), 8.28 (d, J = 8.9 Hz, 1 H), 7.66 (d, J = 8.7 Hz, 1H), 7.44 (m, 2H), 7.33 (m, 1H), 7.23 (m, 1H), 7.08 (dd, J = 2.5, 8.9 Hz, 1H), 4.18 (q, J = 7.5, 2H), 3.89 (s, 3H), 3.85 (m, 2H), 2.90 (m, 2H), 2.52 (m, 1H), 2.14 (m, 4H), 1.29 (t, J = 7.5Hz, 3 H).

Example 41 1- [2- (5-Methoxy-benzimidazol-1-yl] -quinolin-8-yl] -piperidine-4-carboxylic acid

Ethyl 1- [2- (5-methoxy-benzimidazol-1-yl] -quinolin-8-yl] -piperidine-4-carboxylate 40 (28 mg, 0.065 mmol) was dissolved in 1 ml of ethanol (EtOH) To this solution was added 1 ml of 1 N aqueous NaOH and the mixture was then heated to 60 ° C and reacted at that temperature overnight The reaction mixture was then cooled to ambient temperature and partitioned between 10% aqueous citric acid and ethyl acetate was washed again with 10% aqueous citric acid and then three more times with water The ethyl acetate layer was dried over Na ₂ SO ₄ , filtered and concentrated to give 7 mg of the title compound 41 as a yellow solid.
CI m / z 403 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.94 (s, 1 H), 8.73 (d, J = 9.2 Hz, 1 H), 8.40 (d, J = 8.9 Hz, 1 H), 7.90 (d, J = 8.9 Hz, 1H), 7.55 (m, 1H), 7.47 (m, 1H), 7.31 (m, 1H), 7.23 (d, J = 2.3Hz, 1H), 7.07 (dd, J = 2.4, 9.0Hz, 1H), 3.87 (s, 3H), 3, 79 (m, 2H), 2.85 (m, 2H), 2.50 (m, 1H), 2.08 (m, 4H).

Example 42 4-Dimethylaminomethyl-1- [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ol

Example 42A

5- (2-methoxy-ethoxy) -2-nitro-phenylamine

4-Amino-3-nitrophenol (58.53 g, 379.7 mmol) was dissolved in 600 ml of anhydrous DMF under an atmosphere of dry N ₂ and the solution was stirred mechanically. The reaction mixture was then cooled to 0 ° C and to this mixture were added Cs ₂ CO ₃ (177.4 g, 455.7 mmol), sodium iodide (5.7 g, 37.9 mmol) and 2-bromoethyl methyl ether (39.3 ml, 417.7 mmol). After stirring for 15 min, the reaction mixture was then warmed to ambient temperature and then stirred overnight. The reaction mixture is then poured into 6 liters of water. The precipitate was recovered by suction filtration. The wet precipitate was taken up in toluene and then concentrated under vacuum to remove the water. Finally, the solid was recrystallized from 2-propanol to give 57.93 g of 5- (2-methoxyethoxy) -2-nitro-phenylamine 42A as an orange solid. A second batch of 12.5 g of compound 42A was also obtained.

Example 42B

4-dimethylaminomethyl-1- [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ol

The procedure used for Example 24 was followed, but using 5- (2-methoxy-ethoxy) -2-nitro-phenylamine 42A instead of 4-methoxy-2-nitroaniline in Example 1B to give the title compound 42 as a yellow solid was obtained.
CI m / z 476 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 8.85 (s, 1H), 8.55 (d, J = 9.1 Hz, 1H), 8.29 (d, J = 8.7 Hz, 1 H), 7.76 (d, J = 8.7 Hz, 1 H), 7.43 (m, 2 H), 7.27 (d, J = 7.5 Hz, 1 H), 7, 21 (d, J = 2.5Hz, 1H), 7.00 (dd, J = 2.5, 9.0Hz, 1H), 4.13 (m, 2H), 3.77 ( m, 2H), 3.44 (s, 3H), 3.32 (m, 2H), 3.16 (m, 2H), 2.42 (s, 2H), 2.38 ( s, 6H), 1.97 (m, 2H), 1.75 (m, 2H).

Example 43 N- {1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -acetamide

1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine 1 (100 mg, 0.268 mmol) and sodium cyanate (35 mg, 0.536 mmol) were dissolved in 1 ml AcOH dissolved under an atmosphere of dry N ₂ . The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then concentrated in vacuo and concentrated between DCM and saturated aqueous NaHCO ₃ . The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to a yellow foam which was chromatographed on flash silica gel eluting with MeOH / NH ₄ OH / DCM (2 / 0.2 / 97.8) to give the title compound 43 was obtained.
CI m / z 416 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.63 (s, 1 H), 8.30 (m, 2 H), 7.66 (d, J = 8.7 Hz, 1 H), 7.43 ( m, 2 H), 7.33 (d, J = 2.5 Hz, 1 H), 7.23 (dd, J = 1.7, 7.1 Hz, 1 H), 7.03 (dd, J = 2.5, 9.0 Hz, 1H), 5.64 (brd, J = 8.3 Hz, 1H), 4.03 (m, 1H), 3.89 (s, 3H ), 3.84 (m, 2H), 2.93 (m, 2H), 2.16 (m, 2H), 2.02 (s, 3H), 1.88 (m, 2H ).

Example 44 N- {1- [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -acetamide

The procedure used for Example 43 was followed except that 1- [2- (5-cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine 32 was used instead of 1- [2- (5 -Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine 1 to give the title compound 44 as a yellow solid.
CI m / z 456 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.61 (s, 1 H), 8.33 (d, J = 8.7 Hz, 1 H), 8.28 (d, J = 8.7 Hz, 1 H), 7.65 (d, J = 8.7Hz, 1H), 7.45 (m, 2H), 7.28 (d, J = 2.1Hz, 1H), 7.22 (m, 1H), 7.07 (dd, J = 1.5, 8.7Hz, 1H), 5.63 (brd, J = 8.3Hz, 1H), 4.03 (m , 1H), 3.88 (d, J = 7.0 Hz, 2H), 3.85 (m, 2H), 2.92 (m, 2H), 2.14 (m, 2H ), 2.04 (s, 3H), 1.88 (m, 2H), 1.33 (m, 1H), 0.67 (m, 2H), 0.38 (m, 2H ).

Example 45 1- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ol

The procedure used for Example 19 was followed, but using 5- (2-methoxy-ethoxy) -2-nitro-phenylamine 42A instead of 4-methoxy-2-nitroaniline in Example 1B to give the title compound 45 as a yellow solid has been.
CI m / z 419 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.62 (s, 1 H), 8.39 (d, J = 9.1 Hz, 1 H), 8.24 (d, J = 8.7 Hz, 1 H), 7.62 (d, J = 8.7Hz, 1H), 7.43 (m, 2H), 7.31 (d, J = 2.1Hz, 1H), 7.23 (m, 1H), 7.10 (m, 1H), 4.17 (m, 2H), 3.93 (m, 1H), 3.77 (m, 2H), 3.71 (m, 2H), 3.44 (s, 3H), 3.04 (m, 2H), 2.47 (brd, J = 3.3Hz, 1H), 2.14 (m, 2H), 1.97 (m, 2H).

Example 46 {1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -urea

1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine 1 (150 mg, 0.402 mmol) and 1,1'-carbonyldiimadzole (78 mg, 0; 48 mmol) were dissolved in 1 ml of anhydrous THF under an atmosphere of dry N ₂ . The reaction mixture was stirred for 2 h at ambient temperature. 1.0 ml of concentrated ammonium hydroxide (NH ₄ OH) was then added to the reaction mixture, which was then stirred overnight. The reaction mixture was then partitioned between DCM and water. The DCM layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was chromatographed over flash silica gel eluting with MeOH / DCM (5/95) to give 15 mg of the title compound 46 as a white solid.
CI m / z 417 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 8.89 (s, 1 H), 8.59 (d, J = 8.9 Hz, 1 H), 8.36 (J = 8.9 Hz, 2 H ), 7.85 (d, J = 8.7Hz, 1H), 7.74 (brs, 1H), 7.53 (d, J = 8.1Hz, 1H), 7.45 ( m, 1H), 7.30 (d, J = 7.5 Hz, 1H), 7.23 (m, 1H), 7.05 (m, 1H), 3.86 (s, 3 H), 3.73 (m, 2H), 3.66 (m, 1H), 2.87 (m, 2H), 2.08 (m, 2H), 1.83 (m, 2 H).

Example 47 4-Aminomethyl-1- {2- [5- (pyridin-2-ylmethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ol

Example 47A

2-Nitro-4- (pyridin-2-ylmethoxy) -phenylamine

4-Amino-3-nitrophenol (5.00 g, 32.4 mmol), Cs ₂ CO ₃ (22.8 g, 70 mmol), sodium iodide (476 mg, 3.20 mmol) and 2-picolyl chloride hydrochloride (11, 2 g, 35 mmol) were added to 20 ml of anhydrous DMF under an atmosphere of dry N ₂ . The reaction mixture was stirred at ambient temperature overnight. The reaction mixture is then poured into water. The precipitate was recovered by suction filtration. The precipitate was partitioned between DCM and 1.0 N aqueous NaOH. The organic layer was washed two more times with 1N aqueous NaOH to remove any unreacted phenol. The organic layer was then washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to yield 7.7 g of a dark red solid. The solid was chromatographed on flash silica gel eluting with EtOAc / DCM (20/80) to give 3.7 g of the title compound 47A as an orange solid.

Example 47B

4-Aminomethyl-1- {2- [5- (pyridin-2-ylmethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ol

The procedure used for Example 26 was followed, but using 2-nitro-4- (pyridin-2-ylmethoxy) -phenylamine 47A instead of 4-methoxy-2-nitroaniline in Example 1B to give the title compound 47.
CI m / z 481 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.64 (s, 1 H), 8.60 (dd, J = 0.8, 5.0 Hz, 1 H), 8.31 (d, J = 9, 1 Hz, 1 H), 8.27 (d, J = 8.7 Hz, 1 H), 7.68 (m, 1 H), 7.63 (d, J = 9.1 Hz, 1 H) 7.55 (d, J = 7.9Hz, 1H), 7.44 (m, 2H), 7.38 (d, J = 2.1Hz, 1H), 7.27 (m, 1 H), 7.24 (m, 1H), 7.12 (m, 1H), 5.27 (s, 2H), 3.67 (m, 2H), 3.22 (m, 2H), 2.78 (s, 2H), 2.40 (brs, 3H), 1.96 (m, 2H), 1.81 (m, 2H).

Example 48 Cyclopropyl- (1- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -amine

The procedure used for Example 20 was followed, but using 5- (2-methoxy-ethoxy) -2-nitro-phenylamine 42A instead of 4-methoxy-2-nitroaniline in Example 1B to give the title compound 48 as a yellow solid has been.
CI m / z 458 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.65 (s, 1 H), 8.40 (d, J = 8.7 Hz, 1 H), 8.28 (d, J = 8.7 Hz, 1 H), 7.66 (d, J = 8.7Hz, 1H), 7.45 (m, 2H), 7.35 (d, J = 2.5Hz, 1H), 7.25 (m, 1H), 7.15 (m, 1H), 4.22 (m, 2H), 3.82 (m, 2H), 3.80 (m, 2H), 3.47 (s, 3H), 2.88 (m, 3H), 2.27 (m, 1H), 2.18 (m, 2H), 1.85 (m, 2H), 0.50 (m, 2H), 0.47 (m, 2H).

Example 49 (1- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -dimethylamine

The procedure used for Example 4 was followed, but using 5- (2-methoxy-ethoxy) -2-nitro-phenylamine 42A instead of 4-methoxy-2-nitroaniline in Example 1B to give the title compound 49.
CI m / z 446 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.59 (s, 1 H), 8.35 (d, J = 8.7 Hz, 1 H), 8.18 (d, J = 8.7 Hz, 1 H), 7.57 (d, J = 8.7Hz, 1H), 7.38 (m, 2H), 7.28 (d, J = 2.5Hz, 1H), 7.15 (d, J = 2.5, 6.2 Hz, 1H), 7.06 (m, 1H), 4.18 (m, 2H), 3.94 (m, 2H), 3, 75 (m, 2H), 3.42 (s, 3H), 2.72 (m, 2H), 2.40 (m, 1H), 2.34 (s, 6H), 1, 95 (m, 4H).

Example 50 (1- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -methylamine

The procedure used for Example 22 was followed, except using 5- (2-methoxy-ethoxy) -2-nitro-phenylamine 42A instead of 4-methoxy-2-nitroaniline in Example 1B to give the title compound 50.
CI m / z 432 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.62 (s, 1 H), 8.37 (d, J = 9.1 Hz, 1 H), 8.23 (d, J = 8.7 Hz, 1 H), 7.61 (d, J = 8.7Hz, 1H), 7.42 (m, 2H), 7.31 (d, J = 2.1Hz, 1H), 7.20 (d, J = 3.0, 5.8Hz, 1H), 7.11 (dd, J = 2.5, 9.1Hz, 1H), 4.18 (m, 2H), 3 , 88 (m, 2H), 3.76 (m, 2H), 3.45 (s, 3H), 2.85 (m, 2H), 2.59 (m, 1H), 2 , 47 (s, 3H), 2.18 (brs, 1H), 2.11 (m, 2H), 1.75 (m, 2H).

Example 51 (1- {2- [5- (3-Dimethylamino-propoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -dimethylamine

The procedure used for Example 4 was followed except that 1- {2- [5- (3-dimethylamino-propoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine 39 was used instead of 1 - [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine 1 to give the title compound 51 as a white solid.
CI m / z 473 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 8.87 (s, 1 H), 8.61 (d, J = 9.1 Hz, 1 H), 8.31 (d, J = 8.7 Hz, 1 H), 7.78 (d, J = 8.7 Hz, 1 H), 7.48 (d, J = 6.4 Hz, 1 H), 7.42 (m, 1 H), 7, 21 (m, 2H), 7.05 (m, 1H), 4.05 (m, 2H), 3.82 (m, 2H), 3.19 (m, 1H), 2.65 (m, 5H), 2.40 (m, 1H), 2.34 (s, 6H), 1.95 (m, 4H).

Example 52 {1- [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -methylamine

Example 52A

4-cyclopropylmethoxy-2-nitro-phenylamine

4-Amino-3-nitrophenol (13.3 g, 84.8 mmol), Cs ₂ CO ₃ (33.2 g, 102 mmol) and cyclopropylmethylbromide (9.1 mL, 93.3 mmol) were added to 30 mL of anhydrous DMF is added under an atmosphere of dry N ₂ . The reaction mixture was stirred at ambient temperature overnight. The reaction mixture is then poured into water. The precipitate was recovered by suction filtration. The precipitate was partitioned between DCM and 1.0 N aqueous NaOH. The organic layer was washed two more times with 1N aqueous NaOH to remove any unreacted phenol. The organic layer was then washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to yield 18.6 g of the title compound 52A as an orange solid.

Example 52B

{1- [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -methylamine

The procedure used for Example 22 was followed, but using 4-cyclopropylmethoxy-2-nitro-phenylamine 52A instead of 4-methoxy-2-nitroaniline in Example 1B to give the title compound 52.
CI m / z 374 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.63 (s, 1 H), 8.38 (d, J = 9.1 Hz, 1 H), 8.28 (d, J = 8.7 Hz, 1 H), 7.65 (d, J = 8.7Hz, 1H), 7.46 (m, 2H), 7.30 (d, J = 2.5Hz, 1H), 7.24 (m, 1H), 7.06 (m, 1H), 3.89 (m, 4H), 2.90 (m, 2H), 2.71 (m, 1H), 2.55 (s, 3H), 2.16 (m, 2H), 2.00 (brs, 1H), 1.89 (m, 2H), 1.30 (m, 1H), 0.64 (m, 2H), 0.38 (m, 2H).

Example 53 {1- [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -dimethylamine

The procedure used for Example 4 was followed except that {1- [2- (5-cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -methylamine 52 was used in place of 1- [ 2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine 1 was used to give the title compound 53.
CI m / z 442 [M + 1]; ¹ H-NMR _(CDCl3) δ S 8.65 (s, 1 H), 8.38 (d, J = 9.0 Hz, 1 H), 8.30 (d, J = 9.0 Hz, 1 H), 7.69 (d, J = 8.7 Hz, 1 H), 7.48 (m, 2 H), 7.31 (d, J = 2.3 Hz, 1 H), 7, 24 (m, 1H), 7.09 (d, J = 2.3, 9.0 Hz, 1H), 4.03 (m, 2H), 3.89 (d, J = 6.8 Hz, 2H), 2.83 (m, 2H), 2.55 (m, 1H), 2.44 (s, 6H), 2.06 (m, 4H), 1.30 ( m, 1H), 0.68 (m, 2H), 0.39 (m, 2H).

Example 54 2-Amino-N- (1- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -acetamide

N- (tert-butoxycarbonyl) glycine (105 mg, 0.600 mmol) was dissolved in 3 mL DCM under an atmosphere of dry N ₂ . To this mixture was added 1,1'-cabonyldiimdazole (100 mg, 0.61 mmol) and the reaction mixture was stirred at ambient temperature for 30 min. To this solution was then added 4-dimethylaminopyridine (8.0 mg, 0.065 mmol) and 1- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidine 4-ylamine 33 (170 mg, 0.408 mmol). The reaction mixture was then stirred overnight at ambient temperature. The reaction mixture was then partitioned between DCM and saturated aqueous NaHCO ₃ . The organic layer was obtained and washed again with saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a yellow foam. The residue was chromatographed on flash silica gel eluting with MeOH / DCM (3/97) to give 182 mg of a yellow residue. The residue was dissolved in 0.5 ml of TFA and stirred at ambient temperature for 30 minutes under an atmosphere of dry N ₂ . The reaction mixture was then concentrated under vacuum and then partitioned between 0.1 N aqueous NaOH. The organic layer was obtained and washed again with 0.1 N aqueous NaOH, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a yellow foam. The foam was chromatographed on flash silica gel eluting with MeOH / DCM (5/95) to give 75 mg of the title compound 54 as a yellow solid.
CI m / z 475 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.62 (s, 1 H), 8.31 (d, J = 8.7 Hz, 1 H), 8.27 (d, J = 8.7 Hz, 1 H), 7.64 (d, J = 8.7Hz, 1H), 7.44 (m, 2H), 7.38 (brd, J = 7.9Hz, 1H), 7.32 (d, J = 2.1Hz, 1H), 7.22 (m, 1H), 7.06 (d, J = 2.5, 9.2Hz, 1H), 4.20 (m , 2H), 4.02 (m, 1H), 3.86 (m, 2H), 3.78 (m, 2H), 3.46 (s, 3H), 3.37 (s , 2H), 2.94 (m, 2H), 2.13 (m, 2H), 1.90 (m, 2H), 1.74 (brs, 2H).

Example 55 - (S) -2-Amino-N- (1- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) propionamide

The procedure used for Example 54 was followed except that N- (tert-butoxycarbonyl) -L-alanine was used in place of N- (tert-butoxycarbonyl) glycine to give the title compound 55 as a yellow solid.
CI m / z 489 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.61 (s, 1 H), 8.27 (d, J = 8.7 Hz, 1 H), 8.25 (d, J = 9.1 Hz, 1 H), 7.63 (d, J = 8.7Hz, 1H), 7.42 (m, 3H), 7.30 (d, J = 2.5Hz, 1H), 7.22 (dd, J = 2.1, 8.7 Hz, 1H), 7.07 (d, J = 2.5, 8.7 Hz, 1H), 4.17 (m, 2H), 3 , 95 (m, 1H), 3.85 (m, 2H), 3.77 (m, 2H), 3.50 (m, 1H), 3.43 (s, 3H), 2 , 91 (m, 2H), 2.10 (m, 2H), 1.85 (m, 4H), 1.34 (d, J = 6.7Hz, 3H).

Example 56 - (R) -2-Amino-N- (1- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -propinamid

The procedure used for Example 54 was followed except that N- (tert-butoxycarbonyl) -D-alanine was used instead of N- (tert-butoxycarbonyl) glycine to give the title compound 56 as a yellow solid.
CI m / z 489 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.63 (s, 1 H), 8.26 (m, 2 H), 7.65 (d, J = 8.7 Hz, 1 H), 7.44 ( m, 2 H), 7.38 (brd, J = 8.7 Hz, 1 H), 7.33 (d, J = 2.5 Hz, 1 H), 7.22 (dd, J = 2, 1, 7.0 Hz, 1H), 7.10 (d, J = 2.5, 8.7 Hz, 1H), 4.20 (m, 2H), 3.99 (m, 1H ), 3.86 (m, 2H), 3.79 (m, 2H), 3.50 (m, 1H), 3.46 (s, 3H), 2.96 (m, 2H ), 2.12 (m, 2H), 1.88 (m, 2H), 1.52 (brs, 2H), 1.35 (d, J = 7.1Hz, 3H).

Example 57 2-Amino-N- (1- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -isobutyramide

N- (tert-butoxycarbonyl) glycine (73 mg, 0.36 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (69 mg, 0.36 mmol) were dissolved in 1 mL of anhydrous DMF under an atmosphere of dry N ₂ and stirred at ambient temperature for 30 min. Triethylamine (167 μl, 1.24 mmol) and 1- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine 33 (146 mg , 0.35 mmol) were then added to the reaction mixture, which was then stirred overnight. The reaction mixture was then partitioned between DCM and saturated aqueous NaHCO ₃ . The organic layer was obtained and washed two more times with saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a yellow oil. The residue was chromatographed on flash silica gel eluting with a gradient of DCM to MeOH / DCM (2/98) to give 30 mg of a yellow residue. The residue was dissolved in 0.25 ml of TFA and stirred at ambient temperature for 30 minutes under an atmosphere of dry N ₂ . The reaction mixture was then concentrated under vacuum and then partitioned between 0.1 N aqueous NaOH. The organic layer was obtained and washed again with 0.1 N aqueous NaOH, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound 57 as a yellow residue.
CI m / z 503 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.70 (s, 1 H), 8.29 (d, J = 8.7 Hz, 1 H), 8.21 (d, J = 9.1 Hz, 1 H), 7.66 (m, 2H), 7.44 (m, ZH), 7.25 (d, J = 2.5Hz, 1H), 7.21 (dd, J = 2.6 , 9.1 Hz, 1H), 7.12 (m, 1H), 4.19 (m, 2H), 3.95 (m, 1H), 3.88 (m, 2H), 3.79 (m, 2H), 3.46 (s, 3H), 2.93 (m, 2H), 2, 09 (m, 2H), 1.90 (m, 2H), 1.49 (s, 6H).

Example 58 1- (1- {1- [2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamino) -2-methyl-propan-2-one oil

Example 58A

(1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamino) -acetic acid ethyl ester

Ethyl bromoacetate (80 μl, 0.710 mmol), diisopropylethylamine (180 μl, 1.00 mmol) and 1- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} - piperidin-4-ylamine 33 (270 mg, 0.647 mmol) was dissolved in 3 mL of anhydrous DCM under an atmosphere of dry N ₂ and stirred overnight at ambient temperature. The reaction mixture was then partitioned between DCM and 0.1 N aqueous NaOH. The organic layer was obtained and washed successively with 0.1 N aqueous NaOH and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a yellow residue. The residue was chromatographed on flash silica gel eluting with MeOH / DCM (2/98) to give 220 mg of the title compound 58A.

Example 58B

1- (1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamino) -2-methyl-propan-2-ol

(1- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamino) -acetic acid, ethyl ester (110 mg, 0.218 mmol) 58A was added in 2 Anhydrous THF was dissolved under an atmosphere of dry N ₂ . The reaction mixture was cooled to -78 ° C and then treated with 260 ul of a solution of 1.0 M methylmagnesium bromide in THF. The reaction mixture was slowly warmed to ambient temperature and stirred overnight. The reaction mixture was then partitioned between DCM and saturated aqueous NaHCO ₃ . The organic layer was obtained and washed again with saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a yellow residue. The residue was chromatographed on flash silica gel eluting with MeOH / DCM / NH ₄ OH (2 / 97.9 / 0.1) to give 20 mg of the title compound 58 as a yellow residue.
CI m / z 490 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.65 (s, 1 H), 8.35 (d, J = 9.1 Hz, 1 H), 8.28 (d, J = 8.7 Hz, 1 H), 7.66 (d, J = 8.7Hz, 1H), 7.44 (m, 2H), 7.33 (d, J = 2.5Hz, 1H), 7.22 (m, 1H), 7.12 (m, 1H), 4.21 (m, 2H), 3.88 (m, 2H), 3.80 (m, 2H), 3.47 (s, 3H), 2.88 (m, 2H), 2.67 (m, 1H), 2.62 (s, 2H), 2.13 (m, 2H), 1.78 (m, 2H), 1.19 (s, 6H).

Example 59 (1- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -pyridin-2-ylmethyl-amine

1- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine 33 (50 mg, 0.119 mmol) and pyridine-2-carbaldehyde ( 11 μl, 0.119 mmol) were dissolved in a solution of 2 ml EtOH and 500 μl DCE dissolved under an atmosphere of dry N ₂ . The reaction mixture was then heated to reflux temperature and stirred at this temperature for 1.5 h. The reaction mixture was then cooled to ambient temperature and NaBH ₄ (14 mg, 0.357 mmol) added. The reaction mixture was stirred at ambient temperature overnight. The solvent was removed in vacuo and the resulting residue was partitioned between DCM and 0.1 1 N aqueous NaOH. The DCM layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 47 mg of the title compound 59 as a yellow residue.
CI m / z 509 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.63 (s, 1 H), 8.55 (m, 1 H), 8.39 (d, J = 9.1 Hz, 1 H), 8.26 ( d, J = 8.7Hz, 1H), 7.65 (m, 2H), 7.44 (m, 2H), 7.36 (d, J = 8.9Hz, 1H), 7.32 (d, J = 2.5Hz, 1H), 7.22 (m, 1H), 7.12 (m, 2H), 4.20 (m, 2H), 4.01 (s, 2H), 3.89 (m, 2H), 3.79 (m, 2H), 3.46 (s, 3H), 2.90 (m, 2H), 2.77 (m, 1H), 2.13 (m, 2H), 1.88 (m, 3H).

Example 60 (1- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -pyridin-3-ylmethyl-amine

The procedure used for Example 59 was followed except that pyridine-3-carbaldehyde was used instead of pyridine-2-carbaldehyde to give the title compound 60 as a yellow residue.
CI m / z 509 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.65 (s, 1 H), 8.59 (d, J = 2.7 Hz, 1 H), 8.50 (dd, J = 2.7, 5, 0, 1 H), 8.38 (d, J = 8.7 Hz, 1 H), 8.29 (d, J = 8.7 Hz, 1 H), 7.76 (m, 1 H), 7.67 (m, 1H), 7.45 (m, 2H), 7.34 (d, J = 2.5Hz, 1H), 7.27 (m, 1H), 7.22 (m, 1H), 7.12 (dd, J = 2.5, 8.7, 1H), 4.22 (m, 2H), 3.91 (s, 2H), 3.88 (m, 2H), 3.80 (m, 2H), 3.47 (s, 3H), 2.90 (m, 2H), 2.75 (m, 1H), 2.14 (m, 2H), 1.85 (m, 2H), 1.75 (brs, 1H).

Example 61 4- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -phenol

Example 61A

N- (2-bromo-phenyl) -3-phenyl-acrylamide

2-Bromoaniline (48.41 g, 281.4 mmol) was dissolved in 500 mL of anhydrous DCM under an atmosphere of dry N ₂ .

Pyridine (45.5 mL, 563 mmol) was then added and the reaction mixture was then cooled to 0 ° C, after which cinnamyl chloride (46.9 g, 281.4 mmol) was added. The reaction mixture was slowly warmed to ambient temperature and then stirred at ambient temperature overnight. The reaction mixture was diluted with 300 mL of saturated aqueous NaHCO ₃ and then extracted with DCM. The DCM layer was then washed three times with 10% aqueous NaHSO _{4 followed} by saturated aqueous NaHCO ₃ and finally brine. The DCM layer was then over Na ₂ SO ₄ dried, filtered and concentrated in vacuo to give 85.08 g of a tan solid as the title compound 61A.

Example 61B

8-Bromo-quinolin-2-ol

N- (2-Bromo-phenyl) -3-phenyl-acrylamide 61A (85.0 g, 281.3 mmol) was dissolved in 500 mL of chlorobenzene under an atmosphere of dry N ₂ . Aluminum trichloride (187.5 g, 1.40 mmol) was then added to the solution and the reaction mixture was then heated to 90 ° C for 3 h, after which the temperature was raised to 120 ° C. After stirring for 1 h at 120 ° C, another 40 g of aluminum trichloride were added and the reaction mixture stirred for a further hour. The reaction mixture was then cooled to ambient temperature and then poured slowly into a solution of 2L of ice water and 1L DCM. The DCM layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a volume of ~ 100 ml. The pink precipitate was collected and washed with hexanes and then dried to give 44.1 g of the title compound 61B.

Example 61C

Trifluoro-methanesulfonic acid 8-bromo-quinolin-2-yl ester

8-Bromo-quinolin-2-ol 61B (24.4 g, 109 mmol) and 2,6-dimethylpyridine (19 mL, 163 mmol) were dissolved in 500 mL of anhydrous DCM under an atmosphere of dry N ₂ . The reaction mixture was then cooled to 0 ° C and trifluoromethanesulfonic anhydride (22.0 mL, 131 mmol) was added dropwise. Upon completion of the addition, the reaction mixture was warmed to ambient temperature and stirred for 1 h. The reaction mixture was then quenched with water and partitioned between DCM and aqueous NaHCO ₃ . The DCM layer was then washed four times with 10% aqueous citric acid, twice with aqueous NaHCO ₃ and once with brine. The DCM layer was then dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound 61C.

Example 61D

(8-Bromo-quinolin-2-yl) - [4- (2-methoxy-ethoxy) -2-nitro-phenyl] -amine

Trifluoro-methanesulfonic acid 8-bromo-quinolin-2-yl ester 61C (40.8 g, 114 mmol) and 5- (2-methoxyethoxy) -2-nitro-phenylamine 42A (25.2, 119 mmol) were dissolved in 300 ml of toluene under an atmosphere of dry N _2. To this solution was added Cs ₂ CO ₃ (49.3 g, 151 mmol), racemic 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP) (3.91 g, 6.50 mmol) and Tris (dibenzylideneacetone) dipalladium (0) (1.98 g, 2.16 mmol) was added and the reaction mixture was heated to 80 ° C and reacted at this temperature overnight. The mixture was then cooled to ambient temperature and concentrated in vacuo, treated with DCM, filtered and concentrated in vacuo to give a red solid. The solid was triturated with EtOAc and dried under vacuum to give 22.0 g of the title compound 61D.

Example 61E

N ¹ - (8-bromo-quinolin-2-yl) -4- (2-methoxy-ethoxy) -benzene-1,2-diamine

(8-Bromo-quinolin-2-yl) - [4- (2-methoxy-ethoxy) -2-nitrophenyl] -amine 61D (22.0 g, 52.6 mmol) was dissolved in a solution of 500 mL EtOH and 100 ml of water suspended under an atmosphere of dry N ₂ . To this heterogeneous solution was added ammonium chloride (1.75 g, 63.1 mmol) and iron powder (23.5 g, 421 mmol). The reaction mixture was then heated to 100 ° C and reacted at this temperature for 6 h. The reaction mixture was then cooled to ambient temperature, filtered and the filtrate was concentrated in vacuo. The resulting slurry was partitioned between DCM and water. The DCM layer was then washed two more times with water and once with brine. The DCM layer was then dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 20.5 g of the title compound 61E. This material was used without further purification.

Example 61F

8-bromo-2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] quinoline

N ¹ - (8-Bromo-quinolin-2-yl) -4- (2-methoxy-ethoxy) -benzene-1,2-diamine 61E (20.5 g, 52.7 mmol) and formamidine acetate (6.03 g, 58.0 mmol) were dissolved in 150 ml of 2-methoxyethanol under an atmosphere of dry N ₂ . The reaction mixture was heated to reflux and stirred overnight. The reaction mixture was then cooled to ambient temperature, causing the product to precipitate. The pink solid was collected by suction filtration, washed with 2-methoxyethanol and then dried under vacuum to yield 16.1 g of the title compound 61F. The filtrate was concentrated in vacuo and the resulting residue was chromatographed on flash silica gel eluting with a gradient of DCM to MeOH / DCM (1/99) to give an additional 4.40 g of the title compound 61F.

Example 61G

4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -phenol

8-Bromo-2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinoline 61F (585 mg, 1.47 mmol) was dissolved in 10 mL of dioxane under an atmosphere of dry N ₂ . To this solution were added 4-hydroxyphenylboronic acid (240 mg, 1.74 mmol), potassium phosphate (620 mg, 2.92 mmol) and tetrakis (triphenylphosphine) palladium (0) (85 mg, 0.074 mmol). The reaction mixture was heated to 105 ° C and reacted at this temperature for 48 h. The reaction mixture was then cooled to ambient temperature, concentrated in vacuo, and partitioned between DCM and aqueous saturated NaHCO ₃ . The DCM layer was then washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a yellow residue. The residue was chromatographed on flash silica gel eluting with a MeOH / DCM / NH ₄ OH (2 / 97.9 / 0.1) to give 365 mg of a white foam as the title compound 61.
CI m / z 412 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.64 (s, 1 H), 8.21 (d, J = 8.7 Hz, 1 H), 7.93 (d, J = 9.1 Hz, 1 H), 7.68 (d, J = 7.9Hz, 2H), 7.56 (d, J = 9.1Hz, 1H), 7.49 (m, 3H), 7.20 (d, J = 2.5Hz, 1H), 7.07 (d, J = 7.9Hz, 2H), 6.90 (m, 1H), 4.02 (m, 2H) , 3.65 (m, 2H), 3.37 (s, 3H).

Example 62 [2- (4- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -phenoxy) -ethyl] -dimethylamine

4- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -phenol 61 (100 mg, 0.243 mmol) was dissolved in 600 μl of anhydrous DMF under an atmosphere of dry N ₂ solved. Cs ₂ CO ₃ (237 mg, 0.729 mmol) and (2-chloroethyl) -dimethylamine hydrochloride (39 mg, 267 mmol) were added to the reaction mixture. The reaction mixture was heated to 80 ° C and reacted at this temperature for 3 h. The reaction mixture was partitioned between DCM and 0.1 N aqueous NaOH. The DCM layer was washed two more times with 0.1 N aqueous NaOH, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 125 mg of a brown oil. The oil was dissolved in 1 ml of DCM, to which was added 3.0 ml of a solution of 1N hydrochloric acid (HCl) in ethyl ether. The precipitate was collected, washed with ether, dissolved in methanol and finally concentrated in vacuo to give 92 mg of the bis hydrochloride salt of the title compound 62 as a tan solid.
CI m / z 483 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 10.2 (s, 1H), 8.73 (d, J = 9.1 Hz, 1 H), 8.21 (d, J = 9.1 Hz, 1 H), 8.17 (d, J = 8.7 Hz, 1 H), 8.07 (d, J = 8.3 Hz, 1 H), 7.88 (d, J = 6.2 Hz , 1 H), 7.78 (m, 1 H), 7.64 (d, J = 8.7 Hz, 2 H), 7.34 (d, J = 2, 1 Hz, 1 H), 7 , 21 (d, J = 8.3 Hz, 2H), 7.01 (m, 1H20), 4.46 (m, 2H), 4.22 (m, 2H), 3.80 (m, 2H), 3.69 (m, 2H), 3.44 (s, 3H), 3.04 (s, 6H).

Example 63 2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -8-piperazin-1-yl-quinoline

The procedure used for Example 1 was followed except that 8-bromo-2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinoline 61F was used in place of the trifluoromethanesulfonic acid (2- (5-methoxy) benzimidazol-1-yl) -quinolin-8-yl-ester 1E and tert-butyl-1-piperazine-carboxylate were used in place of piperidine-4-yl-carbamic acid tert-butyl ester in Example 1F to give the title compound 63 as tan Solid was obtained.
CI m / z 404 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.62 (s, 1 H), 8.41 (d, J = 9.1 Hz, 1 H), 8.30 (d, J = 8.7 Hz, 1 H), 7.67 (d, J = 9.1Hz, 1H), 7.48 (m, 2H), 7.34 (d, J = 2.1Hz, 1H), 7.23 (m, 1H), 7.13 (dd, J = 2.5, 9.1Hz, 1H), 4.22 (m, 2H), 3.80 (m, 2H), 3, 46 (s, 3H), 3.42 (m, 4H), 3.25 (m, 4H).

Example 64 [2- (4- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -ethyl] -dimethyl-amine

2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -8-piperazin-1-yl-quinoline 63 (100 mg, 0.248 mmol), 2-dimethylaminoethyl chloride hydrochloride (53 mg, 0.37 mmol) and N, N-diisopropylethylamine (130 μL, 0.743 mmol) were dissolved in 1 mL of ACN under an atmosphere of dry N ₂ . The reaction mixture was heated to 82 ° C and reacted at this temperature overnight. The reaction mixture was then concentrated in vacuo and then partitioned between DCM and 1N aqueous NaOH. The DCM layer was then washed again with 1N aqueous NaOH, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a tan residue. The residue was chromatographed on flash silica gel eluting first with MeOH / DCM (5/95) to remove less polar impurities and then with MeOH / DCM / NH ₄ OH (8 / 91.9 / 0.1) to give the title compound 64 was obtained.
CI m / z 475 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.63 (s, 1 H), 8.44 (d, J = 8.7, 1 H), 8.27 (d, J = 8.7 Hz, 1 H ), 7.66 (d, J = 8.7Hz, 1H), 7.45 (m, 2H), 7.33 (d, J = 2.5Hz, 1H), 7.22 ( m, 1H), 7.12 (m, 1H), 4.22 (m, 2H), 3.81 (m, 2H), 3.47 (s, 3H), 3.46 ( m, 4H), 2.83 (m, 4H), 2.63 (m, 2H), 2.52 (m, 2H) 2.30 (s, 6H).

Example 65 [2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -8- (4-pyridin-2-ylmethyl-piperazin-1-yl) -quinoline

The procedure used in Example 64 was used but using 2-picolyl chloride hydrochloride instead of 2-dimethylaminoethyl chloride hydrochloride to give the title compound 65 as a yellow solid.
CI m / z 495 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.62 (s, 1 H), 8.43 (d, J = 9.1, 1 H), 8.28 (d, J = 9.1 Hz, 1 H ), 7.68 (m, 2H), 7.48 (m, 3H), 7.33 (d, J = 2.1Hz, 1H), 7.23 (m, 2H), 7 , 10 (m, 1H), 4.22 (m, 2H), 3.82 (m, 4H), 3.49 (s, 3H), 3.47-3.49 (m, 4 H), 2.92 (m, 4H).

Example 66 [2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -8- (4-pyridin-3-ylmethyl-piperazin-1-yl) -quinoline

The procedure used in Example 64 was used but using 3-picolyl chloride hydrochloride in place of 2-dimethylaminoethyl chloride hydrochloride to give the title compound 66 as a yellow solid.
CI m / z 495 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.63 (m, 2 H), 8.52 (dd, J = 2.6, 5.0 Hz, 1 H), 8.43 (d, J = 9, 1, 1 H), 8.27 (d, J = 8.7 Hz, 1 H), 7.75 (brd, J = 7.5 Hz, 1 H), 7.66 (d, J = 9, 1 Hz, 1 H), 7.46 (m, 2 H), 7.33 (d, J = 2.1 Hz, 1 H), 7.27 (m, 1 H), 7.22 (m, 1 H), 7.10 (m, 1H), 4.23 (m, 2H), 3.82 (m, 2H), 3.67 (s, 2H), 3.48 (s, 3H), 3.47 (m, 4H), 2.82 (m, 4H).

Example 67 2-Amino-1- (4- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -2-methyl- propane-on-1

The procedure used for Example 54 was followed except that 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -8-piperazin-1-yl-quinoline 63 was used instead of 1- {2- [5 - (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine 33 and N-tert-Boc-α-methylalanine instead of N- (tert-butoxycarbonyl) -glycine to give the title compound 67.
¹ H-NMR _(CDCl3) δ 8.62 (s, 1 H), 8.42 (d, J = 8.7 Hz, 1 H), 8.31 (d, J = 8.7 Hz, 1 H), 7.68 (d, J = 8.7Hz, 1H), 7.46 (m, 2H), 7.34 (d, J = 2.5Hz, 1H), 7.21 (dd, J = 2.2, 7.5 Hz, 1H), 7.11 (dd, J = 2.5, 8.7 Hz, 1H), 4.22 (m, 2H), 4 , 17 (m, 4H), 3.81 (m, 2H), 3.47 (s, 3H), 3.39 (m, 4H), 2.13 (brs, 2H), 1 , 49 (s, 6H).

Example 68 (S) -2-Amino-1- (4- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) - propane-on-1

The procedure used for Example 54 was followed except that 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -8-piperazin-1-yl-quinoline 63 was used instead of 1- {2- [5 - (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine 33 and N- (tert-butoxycarbonyl) -L-alanine instead of N- (tert-butoxycarbonyl) -glycine to give the title compound 68 as a yellow solid.
¹ H-NMR _(CDCl3) δ 8.60 (s, 1 H), 8.40 (d, J = 8.7 Hz, 1 H), 8.30 (d, J = 9.1 Hz, 1 H), 7.67 (d, J = 8.7Hz, 1H), 7.46 (m, 2H), 7.33 (d, J = 2.5Hz, 1H), 7.19 (dd, J = 2.3, 7.5 Hz, 1H), 7.10 (m, 1H), 4.20 (m, 2H), 3.96 (m, 2H), 3, 88 (m, 1H), 3.79 (m, 4H), 3.46 (s, 3H), 3.38 (m, 4H), 2.11 (brs, 2H), 1, 30 (d, J = 7.0 Hz, 3 H).

Example 69 (S) -2-Amino-1- (4- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) - propane-on-1

The procedure used for Example 54 was followed except that 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -8-piperazin-1-yl-quinoline 63 was used instead of 1- {2- [5 - (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine 33 and N- (tert-butoxycarbonyl) -D-alanine instead of N- (tert-butoxycarbonyl) glycine to give the title compound 69 as a yellow solid.
¹ H-NMR _(CDCl3) δ 8.60 (s, 1 H), 8.40 (d, J = 9.1 Hz, 1 H), 8.30 (d, J = 8.7 Hz, 1 H), 7.66 (d, J = 8.7 Hz, 1H), 7.46 (m, 2H), 7.33 (m, 1 Fi), 7.18 (m, 1H), 7.11 (m, 1H), 4.20 (m, 2H), 3.96 (m, 2H), 3.88 (m, 1H), 3.79 (m, 4H), 3.46 (s, 3H), 3.36 (m, 4H), 2.10 (brs, 2H), 1.29 (d, J = 6.2Hz, 3H).

Example 70 2-Amino-1- (4- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -ethanone

The procedure used for Example 54 was followed except that 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -8-piperazin-1-yl-quinoline 63 was used instead of 1- {2- [5 - (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine 33 to give the title compound 70.
¹ H-NMR _(CDCl3) δ 8.59 (s, 1 H), 8.40 (d, J = 8.7 Hz, 1 H), 8.29 (d, J = 8.7 Hz, 1 H), 7.66 (d, J = 8.7 Hz, 1H), 7.51 (dd, J = 2.2, 7.9, 1H), 7.45 (m, 1H), 7.33 (d, J = 2.5 Hz, 1 H), 7.18 (dd, J = 2.2, 7.5 Hz, 1 H), 7.09 (d, J = 2.5, 8.7 Hz, 1H), 4.19 (m, 2H), 3.96 (m, 2H), 3.79 (m, 2H), 3.68 (m, 2H), 3 , 54 (m, 2H), 3.46 (s, 3H), 3.39 (m, 2H), 3.33 (m, 2H), 2.05 (brs, 2H).

Example 71 (1-Amino-cyclopropyl) - (4- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -methanone

The procedure used for Example 54 was followed except that 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -8-piperazin-1-yl-quinoline 63 was used instead of 1- {2- [5 - (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine 33 and 1-tert-butoxycarbonylaminocyclopropanecarboxylic acid were used instead of N- (tert-butoxycarbonyl) -glycine, the Title Compound 71 was obtained.
CI m / z 487 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.62 (s, 1 H), 8.40 (d, J = 9.1 Hz, 1 H), 8.31 (d, J = 8.7 Hz, 1 H), 7.68 (d, J = 8.7 Hz, 1H), 7.52 (dd, J = 2.2, 7.9, 1H), 7.45 (m, 1H), 7.34 (d, J = 2.1 Hz, 1 H), 7.20 (dd, J = 2.2, 7.5 Hz, 1 H), 7.10 (m, 1 H), 4, 20 (m, 2H), 4.00 (m, 4H), 3.79 (m, 2H), 3.46 (s, 3H), 3.39 (m, 4H), 2, 02 (brs, 2H), 1.04 (m, 2H), 0.84 (m, 2H).

Example 72 2- (4- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -ethylamine

2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -8-piperazin-1-yl-quinoline 63 (100 mg, 0.248 mmol) and tert -Butyl N- (2-oxoethyl) carbamate (39.5, 0.248 mmol) was dissolved in 1 ml of methanol under an atmosphere of dry N ₂ . To this solution was added 200 μl of AcOH followed by NaCNBH ₃ (19 mg, 0.297 mmol) and the reaction was then stirred overnight at ambient temperature. The reaction mixture was then concentrated in vacuo and the resulting residue was partitioned between DCM and 1N aqueous NaOH. The DCM layer was then washed successively with 1N aqueous NaOH and brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to give a yellowish green film. The film was then dissolved in a solution of 1 ml of DCM and 2 ml of TFA under an atmosphere of dry N ₂ . The reaction mixture was stirred at ambient temperature for 30 minutes after which it was concentrated in vacuo. The resulting residue was partitioned between 0.1 N aqueous NaOH. The DCM layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a green film. The film was chromatographed on flash silica gel eluting with MeOH / DCM (5/95) to remove the less polar impurities and then MeOH / DCM / NH ₄ OH (5 / 94.9 / 0.1) to give 71 mg of the title compound 72 were.
CI m / z 447 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.63 (s, 1 H), 8.45 (d, J = 9.1 Hz, 1 H), 8.27 (d, J = 8.7 Hz, 1 H), 7.66 (d, J = 8.7Hz, 1H), 7.46 (m, 2H), 7.33 (d, J = 2.5Hz, 1H), 7.22 (m, 1H), 7.11 (dd, J = 2.5Hz, 8.7Hz, 1H), 4.20 (m, 2H), 3.80 (m, 2H), 3 , 47 (s, 3H), 3.43 (m, 4H), 2.89 (t, J = 5.8Hz, 2H), 2.80 (m, 4H), 2.59 ( t, J = 5.8 Hz, 2H), 2.17 (brs, 2H).

Example 73 (R) -2-Amino-1- (4- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) - propane-1-ol

The procedure used for Example 72 was followed except that tert-butyl- (S) - (-) - 4-formyl-2,2-dimethyl-3-oxazolidinecarboxylate instead of tert-butyl-N- (2-oxoethyl) - carbamate to give the title compound 73.
CI m / z 477 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.61 (s, 1 H), 8.43 (d, J = 9.1 Hz, 1 H), 8.27 (d, J = 8.7 Hz, 1 H), 7.64 (d, J = 8.7Hz, 1H), 7.45 (m, 2H), 7.32 (d, J = 2.1Hz, 1H), 7.20 (dd, J = 2.6, 7.1 Hz, 1 H), 7.10 (dd, J = 2.5 Hz, 9.1 Hz, 1 H), 4.20 (m, 2 H), 3.80 (m, 2H), 3.66 (m, 2H), 3.46 (s, 3H), 3.45 (m, 4H), 3.25 (m, 1H), 2.82 (m, 4H), 2.65 (m, 1H), 2.50 (m, 3H).

Example 74 3- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperazin-8-yl) -3-azabicyclo [3.1.0] hex -6-ylamine

The procedure used for Example 33 was followed except that (3-azabicyclo [3.1.0] hex-6-yl) -carbamic acid tert -butyl ester in place of piperidine-4-yl-carbamic acid tert-butyl ester in Example 1F to give the title compound 74 as a yellow solid.
¹ H-NMR _(CDCl3) δ 8.59 (s, 1 H), 8.22 (d, J = 8.7 Hz, 1 H), 7.99 (d, J = 9.1 Hz, 1 H), 7.59 (d, J = 8.7Hz, 1H), 7.37 (m, 2H), 7.35 (d, J = 2.5Hz, 1H), 7.09 (dd, J = 2.5, 9.1Hz, 1H), 6.83 (d, J = 7.9Hz, 1H), 4.34 (d, J = 9.6Hz, 2H), 4.20 (m, 2H), 3.80 (m, 2H), 3.46 (s, 3H), 3.42 (d, J = 9.6 Hz, 2H), 2, 93 (brs, 2H), 2.65 (s, 1H), 1.73 (s, 2H).

Example 75 (S) -1- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -pyrrolidin-3-ylamine

The procedure used for Example 33 was followed except that (3S) - (-) - 3- (tert-butoxycarbonylamino) -pyrrolidine was used in place of piperidine-4-yl-carbamic acid tert-butyl ester in Example 1F the title compound 75 was obtained as a tan solid.
¹ H-NMR (CD ₃ OD) δ 8.75 (d, J = 1.7 Hz, 1 H), 8.30 (d, J = 8.7 Hz, 1 H), 8.00 (d, J = 9.1 Hz, 1H), 7.70 (dd, J = 2.1, 8.7 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7 , 24 (m, 2H), 7.04 (dd, J = 2.6, 9.1 Hz, 1H), 6.90 (d, J = 7.9 Hz, 1H), 4.16 (m, 2H), 3.90 (m, 1H), 3.82 (m, 1H), 3.77 (m, 2H), 3.66 (m, 1H), 3.60 (m, 1H), 3.48 (m, 1H), 3.43 (s, 3H), 2.21 (m, 1H), 1.80 (m, 1H).

Example 76 (R) -1- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -pyrrolidin-3-ylamine

The procedure used for Example 33 was followed except that (3R) - (-) - 3- (tert-butoxycarbonyl-amino) -pyrrolidine was used in place of piperidine-4-yl-carbamic acid tert-butyl ester in Example 1F the title compound 76 was obtained as a tan solid.
¹ H-NMR (CD ₃ OD) δ 8.80 (s, 1 H), 8.35 (d, J = 8.7 Hz, 1 H), 8.05 (d, J = 8.7 Hz, 1 H), 7.76 (d, J = 8.7 Hz, 1 H), 7.41 (t, J = 7.9 Hz, 1 H), 7.28 (m, 2 H), 7, 09 (dd, J = 2.5, 9.1Hz, 1H), 6.93 (d, J = 7.5Hz, 1H), 4.18 (m, 2H), 3.91 ( m, 1H), 3.84 (m, 1H), 3.78 (m, 2H), 3.66 (m, 1H), 3.62 (m, 1H), 3.48 ( m, 1H), 3.44 (s, 3H), 2.23 (m, 1H), 1.82 (m, 1H).

Example 77 2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -8-pyridin-3-yl-quinoline

Example 77 A

8-benzyloxy-quinoline-2-ol

2,8-Quinolinediol (133.3 g, 0.827 mol) was dissolved in 800 ml of anhydrous DMF under an atmosphere of dissolved dry N ₂ . To this solution was added potassium carbonate (183 g, 1.32 mol) followed by benzyl bromide (110 ml, 0.909 mol) and the solution was then heated to 65 ° C and reacted at that temperature overnight. The reaction mixture was then poured into 9 liters of water and the resulting solution was stirred at ambient temperature for 5.5 hours, after which it was filtered. The solid was washed with water, recovered and suspended in toluene, and finally the solution was concentrated in vacuo to give 142 g of the title compound 77A.

Example 77B

8-benzyloxy-2-chloro-quinoline

8-Benzyloxy-quinolin-2-ol 77A (142 g, 0.565 mol) was dissolved in 500 ml of DCE under an atmosphere of dry N ₂ . Oxalyl chloride (99 ml, 1.13 mol) and then 1 ml of DMF were added dropwise to this solution. After completion of the addition, the reaction mixture was stirred at ambient temperature for 30 minutes, after which the reaction mixture was heated to 84 ° C. The reaction mixture was stirred for 10 h at this temperature and then concentrated under vacuum. The resulting residue was partitioned between DCM and aqueous saturated NaHCO ₃ . The DCM layer was washed again with aqueous saturated NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a brown solid. The solid was recrystallized from toluene to give two batches (68.3 g and 38.3 g) of the title compound 77B.

Example 77C

(8-Benzyloxy-quinolin-2-yl) - [4- (2-methoxy-ethoxy) -2-nitro-phenyl] -amine

8-Benzyloxy-2-chloro-quinoline 77B (25.53 g, 94.64 mmol) was added to 350 mL of anhydrous toluene under an atmosphere of dry N ₂ . To this solution was added 5- (2-methoxyethoxy) -2-nitro-phenylamine 42A (20.08 g, 94.64 mmol), palladium acetate (433 mg, 1.89 mmol), Cs ₂ CO ₃ (43, 2 g, 132 mmol), phenylboronic acid (584 mg, 4.78 mmol) and 1,2-bis (diphenylphosphino) ethane (2.33 g, 5.68 mmol) and the mixture was then purified by bubbling argon through Deoxygenated for 10 minutes. The reaction mixture was then heated to 95 ° C and reacted at this temperature for 2 hours. The reaction mixture was then diluted (while it was still hot) with 350 mL of DCE and then filtered while still hot. The filter cake was washed with 100 ml of hot DCE. The filtrate was concentrated to ~175 ml, during which time a large amount of precipitate formed. To this mixture was added 400 ml of EtOH and the reaction mixture was stirred overnight. The formed red precipitate was collected by suction filtration and dried under vacuum to give 36.8 g of the title compound as a red solid 77C.

Example 77D

2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-ol

(8-Benzyloxy-quinolin-2-yl) - [4- (2-methoxyethoxy) -2-nitro-phenyl] -amine 77C (36.8 g, 85.4 mmol) was dissolved in 275 mL of EtOH under a vacuum Atmosphere of dry N ₂ suspended. The reaction mixture was then cooled to 0 ° C, after which 119 ml of triethylamine (NEt ₃ ) and then 34 ml of formic acid (slowly) were added. The ice bath was removed and the reaction mixture was then heated to ~ 80 ° C and reacted at this temperature until the nitro group is completely reduced to the amine and the benzyl group is completely removed (as determined by mass spectral analysis), which in this case is ~ 2 h lasted. To this mixture is then added formamidine acetate (11.56 g, 111 mmol) and the reaction temperature was raised to reflux. After several hours more formamidine acetate (3.20 g) was added and the reaction stirred for a further 4 hours while refluxing. The reaction mixture was then cooled to ambient temperature and then filtered through Celite ^™ . The Celite ^™ was washed with large volumes of a 1: 1 MeOH / DCM solution and the combined filtrates were concentrated in vacuo and the solids formed were triturated with 200 mL of EtOH. The solution was filtered and the precipitate was dried under vacuum to give 23.03 g of the title compound 77D as a white solid.

Example 77E

Trifluoro-methanesulfonic acid 2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl ester

2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-ol 77D (23.0 g, 68.6 mmol) was dissolved in a solution of 120 ml of anhydrous DMF and 250 ml of THF dissolved under an atmosphere of dry N ₂ . To this solution was added N-phenyl-bis (trifluoromethanesulfonimide) (26.95 g, 75.5 mmol) and NEt ₃ (6.75 mL, 137.2 mmol). The reaction mixture was stirred overnight at ambient temperature, after which an additional 2.70 g of N-phenyl-bis (trifluoromethanesulfonimide) and 700 μl of NEt _{3 were} added. The reaction mixture was stirred for a further hour and then filtered and the filter cake was washed with ethyl ether. The filter cake was dried under vacuum to give 6.70 g of the title compound 77E as a white solid. A second batch was obtained by concentrating the filtrate to ~ 75 ml. To this solution was added 200 ml of ethyl ether, and the resulting mixture was stirred for 1 hour and then filtered. The filter cake was washed with ethyl ether and then dried under vacuum to give an additional 19.91 g of the title compound 77E for a total of 28.61 g.

Example 77F

2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8-pyridin-3-yl-quinoline

Trifluoro-methanesulfonic acid 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 77E (1.00 g, 2.14 mmol), diethyl (3-pyridyl) borane (620mg, 4.36mmol), lithium chloride (188mg, 4.36mmol) and tetrakis (triphenylphosphine) palladium (0) (248mg, 0.215mmol) were dissolved in a solution of 14mL toluene, 4mL EtOH and 1.5 ml of 2N aqueous sodium carbonate (Na ₂ CO ₃ ) under an atmosphere of dry N ₂ . The reaction mixture was heated to 90 ° C and reacted at this temperature overnight. The reaction mixture was then cooled to ambient temperature, concentrated in vacuo and partitioned between DCM and aqueous saturated NaHCO ₃ . The DCM layer was then washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was chromatographed on flash silica gel, eluting with a gradient of MeOH / DCM (1/99) to MeOH / DCM (2/98) to give 460 mg of the title compound 77.
CI m / z 397 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.86 (d, J = 1.6 Hz, 1 H), 8.67 (dd, J = 1.3, 4.6 Hz, 1 H), 8.56 (s, 1H), 8.35 (d, J = 8.7Hz, 1H), 8.08 (m, 1H), 7.88 (m, 1H), 7.78 (m, 2H), 7.70 (d, J = 8.7Hz, 1H), 7.62 (m, 1H), 7.42 (m, 1H), 7.25 (m, 1H) , 6.84 (dd, J = 2.5Hz, 9.1Hz, 1H), 4.15 (m, 2H), 3.77 (m, 2H), 3.45 (s, 3 H).

Example 78 2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -8- (6-methoxy-pyridin-3-yl-quinoline

Trifluoro-methanesulfonic acid 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 77E (850 mg, 1.82 mmol), 2-methoxy-5-pyridineboronic acid ( Potassium phosphate (K ₂ CO ₃ ) (772 mg, 3.64 mmol) and tetrakis (triphenylphosphine) palladium (0) (208 mg, 0.182 mmol) were dissolved in 5 mL of Dioxane dissolved under an atmosphere of dry N ₂ . The reaction mixture was heated to 100 ° C and reacted at this temperature overnight. The reaction mixture was then cooled to ambient temperature, concentrated in vacuo and partitioned between DCM and aqueous saturated NaHCO ₃ . The DCM layer was then washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was chromatographed on flash silica gel eluting with a gradient of EtOAc / DCM (20/80) to EtOAc / DCM (75/25) to give 856 mg of the title compound 78.
CI m / z 427 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.63 (s, 1 H), 8.39 (d, J = 2.1 Hz, 1 H), 8.31 (d, J = 8.7 Hz, 1 H), 7.96 (m, 1H), 7.91 (d, J = 9.1Hz, 1H), 7.80 (dd, J = 2.2, 8.3Hz, 1H) , 7.72 (m, 2H), 7.56 (m, 1H), 7.24 (m, 1H), 6.87 (m, 1H), 6.83 (d, J = 8 , 7Hz, 1H), 4.14 (m, 2H), 4.00 (s, 3H), 3.76 (m, 2H), 3.44 (s, 3H).

Example 79 4- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -benzoic acid methyl ester

The procedure used for Example 78 was followed, but using 4-methoxycarbonylphenylboronic acid instead of 2-methoxy-5-pyridineboronic acid to give the title compound 79 as a white solid.
CI m / z 454 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.77 (s, 1 H), 8.37 (d, J = 8.7 Hz, 1 H), 8.13 (d, J = 8.3 Hz, 2 H), 7.91 (d, J = 9.1Hz, 1H), 7.88 (dd, J = 2.2, 7.9Hz, 1H), 7.77 (m, 4H) , 7.62 (m, 1H), 7.26 (d, J = 2.1Hz, 1H), 6.82 (dd, J = 2.5, 9.1Hz, 1H), 4 , 16 (m, 2H), 3.99 (s, 3H), 3.77 (m, 2H), 3.46 (s, 3H).

Example 80 1- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -4-methyl-piperidin-4-ylamine

Example 80A

Piperidine-1,4-dicarboxylic acid tert-butyl ester ethyl ester

Piperidine-4-carboxylic acid ethyl ester (9.80 mL, 63.2 mmol) was dissolved in 60 mL DCM at ambient temperature under an atmosphere of dry N ₂ . Di-tert-butyl dicarbonate (13.77 g, 63.16 mmol) was added individually to the reaction mixture, after which the reaction mixture was stirred overnight. The reaction mixture was then partitioned between DCM and saturated aqueous NaHCO ₃ . The DCM layer was washed two more times with saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 16.13 g of the title compound 80A as an oil.

Example 80B

4-methyl-piperidine-1,4-dicarboxylic acid tert-butyl ester ethyl ester

Piperidine-1,4-dicarboxylic acid tert-butyl ester ethyl ester 80A (10.9 g, 42.3 mmol) was dissolved in 44 ml of anhydrous THF under an atmosphere of dry N ₂ . The solution was then cooled to -40 ° C and slowly added with 85 ml of a solution of 1 M lithium bis (trimethylsilyl) amide in tetrahydrofuran. The reaction mixture was stirred at -40 ° C for 1 h, after which iodomethane (5.3 mL, 85 mmol) was added. The solution was allowed to warm to ambient temperature and quenched with water after 1 h. The reaction mixture was partitioned between DCM and aqueous saturated NaHCO ₃ . The DCM layer was washed two more times with aqueous saturated NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound 80B as an orange oil (14.78 g). The compound was used without further purification.

Example 80C

4-methyl-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester

4-Methyl-piperidine-1,4-dicarboxylic acid tert-butyl ester ethyl ester 80B (12.8 g, 47.2 mmol) was dissolved in a solution of 94 mL EtOH and 47 mL 2N aqueous NaOH. The reaction mixture was heated to 60 ° C and reacted at this temperature for 6 h. The reaction mixture was concentrated in vacuo to remove the EtOH. The remaining aqueous solution was washed three times with ethyl ether. The pH was then adjusted to 3 by careful addition of 1N HCl. The aqueous layer was then washed four times with EtOAc. The EtOAc extracts were combined, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 9.54 g of the title compound 80C as a white solid. The compound was used without further purification.

Example 80D

4-carbamoyl-4-methyl-piperidine-1-carboxylic acid tert-butyl ester

4-Methyl-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester 80C (9.54 g, 39.2 mmol) was dissolved in 115 ml of anhydrous THF under an atmosphere of dry N ₂ . The reaction mixture was cooled to 0 ° C after which NEt ₃ (4.50 mL, 47.1 mmol) was added followed by ethyl chloroformate (7.10 mL, 60.0 mmol). The mixture was warmed to ambient temperature and stirred for 15 minutes, after which it was recooled to 0 ° C. To this mixture was added 65 ml of NH ₄ OH. The reaction mixture was warmed to ambient temperature and the THF was removed under vacuum. The resulting aqueous solution was washed three times with DCM. The DCM extracts were combined, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound 80D as an oil (6.19g). The compound was used without further purification.

Example 80E

4-Amino-4-methyl-piperidine-1-carboxylic acid tert-butyl ester

Tert-butyl 4-carbamoyl-4-methyl-piperidine-1-carboxylate 80D (6.19 g, 25.6 mmol), [bis (trifluoroacetoxy) iodo] -benzene (16.5 g, 38.3 mmol) and pyridine (6.20 ml, 76.9 mmol) were dissolved in a solution of 40 ml of ACN and 20 ml of water under an atmosphere of dry N ₂ . The reaction mixture was stirred for 2 h at ambient temperature, after which it was diluted with aqueous 1 N NaOH. The resulting solution was washed three times with DCM. The DCM extracts were combined, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give an oil. The oil was partitioned between DCM and aqueous HCl (pH ~ 3). The aqueous layer was washed two more times with DCM and then basified with 2N aqueous NaOH to ~10 pH. The basic aqueous layer was washed three times with DCM. The DCM extracts were combined, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 4.19 g of the title compound 80E as a yellow oil. The compound was used without further purification.

Example 80F

(4-methyl-piperidin-4-yl) -carbamic acid benzyl ester

Tert -Butyl 4-amino-4-methyl-piperidine-1-carboxylate 80E (4.19 g, 19.6 mmol) was dissolved in a solution of 50 ml of dioxane and 20 ml of aqueous 2N NaOH under an atmosphere of dry N ₂ solved. To this solution was added slowly benzyl chloroformate (5.6 mL, 39 mmol) and the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was concentrated in vacuo. The reaction mixture was dissolved in DCM and washed successively three times with aqueous 1N NaOH. The DCM layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a yellow oil. The oil was dissolved in 15 ml of TFA under an atmosphere of dry N ₂ . The reaction mixture was concentrated in vacuo and partitioned between DCM and 0.1 N aqueous NaOH. The DCM layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 3.06 g of an oil. The oil was chromatographed on flash silica gel eluting with DCM to remove less polar impurities and then MeOH / DCM / NH ₄ OH (20 / 79.9 / 0.1) to give 2.85 g of the title compound 80F as an oil.

Example 80G

1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -4 -methyl-piperidin-4-ylamine

The procedure used for Example 1 was followed except that trifluoromethanesulfonic acid 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 77E was used in place of trifluoromethanesulfonic acid ( 2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl-ester 1E and (4-methyl-piperidin-4-yl) -carbamic acid-benzylester 80F instead of piperidin-4-yl-carbamic acid-tert-butyl ester in Example F to give the title compound 80 as a yellow solid.
CI m / z 432 [M + 1]; ¹ H-NMR (CD ₃ OD) 8.80 (s, 1 H), 8.9 (d, J = 9.1 Hz, 1 H), 8.24 (d, J = 9.1 Hz, 1 H), 7.70 (d, J = 8.7 Hz, 1H), 7.44 (m, 2H), 7.24 (dd, J = 1.2, 8.7 Hz, 1H) , 7.18 (d, J = 2.5 Hz, 1H), 7.00 (m, 1H), 4.12 (m, 2H), 3.76 (m, 2H), 3, 43 (s, 3H), 3.26 (m, 2H), 3.13 (m, 2H), 1.75 (m, 4H), 1.17 (s, 3H).

Example 81 1- [2- (6,7-Dihydro-5,8-dioxa-1,3-diaza-cyclopenta [b] naphthalen-1-yl) -quinolin-8-yl] -piperidin-4-ylamine

Example 81A

8-bromo-2-chloro-quinoline

8-Bromo-quinolin-2-ol 61B (44.11 g, 196.7 mmol) was dissolved in 450 mL of DCE under an atmosphere of dry N ₂ . To this solution was added dropwise oxalyl chloride (65.3 ml, 749 mmol), followed by the addition of 400 μl of dimethylformamide. After completion of the addition, the reaction mixture was heated to reflux temperature and reacted for 3 hours. The reaction mixture was concentrated in vacuo. The resulting residue was partitioned between DCM and saturated aqueous NaHCO ₃ , washed again with saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 48.40 g of the title compound 81A as an orange solid.

Example 81B

6,7-dihydro-1H-5,8-dioxa-1,3-diaza-cyclopenta [b] naphthalene

5-6-Ethylenedioxy-2-mercaptobenzimidazole (1.27 g, 6.10 mmol) and 3.5 mL of Raney ^® nickel (50% slurry in water) were suspended in 30 mL of EtOH under an atmosphere of dry N ₂ , The reaction mixture was heated to 80 ° C and reacted at this temperature for 3 h. The reaction mixture was then filtered through Celite ^™ and the Celite ^™ was then washed with ethanol and DCM. The filtrates were combined and concentrated in vacuo to give 750 mg of the title compound 81B as a foam.

Example 81C

1- (8-Bromo-quinolin-2-yl) -6,7-dihydro-1H-5,8-dioxa-1,3-diaza-cyclopenta [b] naphthalene

6,7-Dihydro-1H-5,8-dioxa-1,3-diaza-cyclopenta [b] naphthalene 81B (600 mg, 3.4 mmol) was dissolved in 15 ml of 1-methyl-2-pyrrolidinone under an atmosphere of dissolved dry N ₂ . To this solution was added 60% sodium hydride in oil (136 mg, 3.40 mmol) and the reaction mixture was stirred for 15 min. 8-Bromo-2-chloro-quinoline 81A (750 mg, 3.10 mmol) was then added to the reaction mixture, which was then heated to 65 ° C and reacted at this temperature overnight. The reaction mixture was then cooled to ambient temperature, partitioned between DCM and saturated aqueous NaHCO ₃ , washed again with saturated aqueous NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and added under Va concentrated to give 1.60 g of an orange solid. The solid was chromatographed on flash silica gel eluting with a gradient of DCM to MeOH / DCM (0.5 / 99.5) to give 700 mg of the title compound 81C as a light yellow solid.

Example 81D

{1- [2- (6,7-dihydro-5,8-dioxa-1,3-diaza-cyclopenta [b] naphthalen-1-yl) -quinolin-8-yl] -piperidin-4-yl} - carbamic acid tert-butyl ester

1- (8-Bromo-quinolin-2-yl) -6,7-dihydro-1H-5,8-dioxa-1,3-diaza-cyclopenta [b] naphthalene 81 C (700 mg, 1, 83 mmol) and tert-butyl piperidine-4-ylcarbamate (733mg, 3.66mmol) were dissolved in 6.0mL of dioxane under an atmosphere of dry N ₂ . To this solution was added Cs ₂ CO ₃ (835 mg, 2.56 mmol), racemic BINAP (68 mg, 0.109 mmol) and tris (dibenzylideneacetone) dipalladium (0) (34 mg, 0.037 mmol) and the reaction mixture was at reflux heated and reacted at this temperature overnight. The mixture was then cooled to ambient temperature, filtered and concentrated in vacuo to yield 1.12 g of an orange film. The film was dissolved in a solution of 5 ml of TFA and 5 ml of DCM under an atmosphere of dry N ₂ . The reaction mixture was stirred at ambient temperature for 30 minutes, after which it was concentrated in vacuo to give a yellow oil. The oil was partitioned between ethyl ether and 0.1 N aqueous HCl. The aqueous layer was then washed with DCM. The aqueous layer was basified to pH ~ 11 with NaOH. The resulting solution was washed three times with DCM. The DCM extracts were combined, dried over Na ₂ SO ₄ , filtered and concentrated to give 500 mg of a yellow solid. The solid was chromatographed on flash silica gel eluting with MeOH / DCM (10/90) to give 127 mg of the title compound 81 as a yellow solid.
CI m / z 402 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 8.63 S (s, 1 H), 8.19 (s, 1 H), 8.08 (d, J = 8.7 Hz, 1 H), 7, 56 (d, J = 9.1Hz, 1H), 7.30 (m, 2H), 7.08 (dd, J = 2.1Hz, 6.7Hz, 1H), 7.06 (s, 1H), 4.21 (m, 4H), 3.57 (m, 2H), 2.63 (m, 3H), 1.86 (m, 2H), 1.73 (m, 2H).

Example 82 4-Cyclopropylaminomethyl-1- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ol

The procedure used for Example 24 was followed except that 5- (2-methoxy-ethoxy) -2-nitro-phenylamine 42A instead of 4-methoxy-2-nitroaniline in Example 1B and cyclopropylamine instead of a 2.0 M solution of dimethylamine in THF to give the title compound 82 as a yellow foam 82.
CI m / z 488 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.63 (s, 1 H), 8.33 (d, J = 9.1 Hz, 1 H), 8.28 (d, J = 8.7 Hz, 1 H), 7.65 (d, J = 8.7Hz, 1H), 7.44 (m, 2H), 7.33 (d, J = 2.1Hz, 1H), 7.27 (m, 1H), 7.08 (m, 1H), 4.21 (m, 2H), 3.81 (m, 2H), 3.68 (m, 2H), 3.47 (s, 3H), 3.22 (m, 2H), 2.80 (brs, 2H), 2.28 (m, 1H), 1.99 (m, 2H), 1.73 (m, 2H), 0.51 (m, 2H), 0.40 (m, 2H).

Example 83 2- {1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yloxy} -ethanol

The procedure used for Example 2 was followed except that 1- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine 33 instead of 1 - [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine 1 to give the title compound 83 as a yellow solid.
CI m / z 404 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 8.96 (s, 1 H), 8.69 (d, J = 8.7 Hz, 1 H), 8.42 (d, J = 8.7 Hz, 1 H), 7.93 (d, J = 8.7 Hz, 1 H), 7.56 (d, J = 6.5 Hz, 1 H), 7.48 (t, J = 7.9 Hz , 1 H), 7.33 (d, J = 7.5 Hz, 1 H), 7.29 (d, J = 2.5 Hz, 1 H), 7.22 (m, 1 H), 4 , 14 (m, 2H), 3.92 (m, 2H), 3.85 (m, 2H), 2.83 (m, 3H), 2.00 (m, 2H), 1 , 83 (m, 2H).

Example 84 1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazole-5-sulfonic acid dimethylamide

Example 84A

4-amino-N, N-dimethyl-3-nitro-benzenesulfonamide

6.00 g (25.0 mmol) of sodium 2-nitroaniline-4-sulfonate was taken up in 25.0 ml of carbon tetrachloride (CCl ₄ ) with 13.0 g (62.4 mmol) of phosphorus pentachloride (PCl ₅ ) and 5 h heated to reflux temperature. The reaction mixture was allowed to cool to room temperature and poured into ice-water. Chloroform (CHCl ₃ ) was added and normal aqueous work up gave a bright yellow solid. Half of the isolated material was taken up in 10.0 ml H ₂ O and cooled to 0 ° C. To this solution was slowly added 44.0 ml (87.5 mmol) of 2.0 M dimethylamine in methanol. After the initial exotherm and gas evolution subsided, the reaction mixture was heated to 80 ° C for 4 hours. The reaction mixture was allowed to cool to room temperature and the pH was adjusted to 3.0 using dilute HCl. The quenched reaction mixture was stirred slowly at room temperature overnight. 1.13 g (4.62 mmol, 37%) of the desired product 84A was collected as a bright yellow solid by filtration.

Example 84B

{1- [2- (5-dimethylsulfamoyl-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -carbamic acid tert-butyl ester

the for example 1 method was followed, except that 4-amino-N, N-dimethyl-3-nitro-benzenesulfonamide 84A instead of 4-methoxy-2-nitroaniline used in Example 1B to give the title compound 84B as a solid.

Example 84C

1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazole-5-sulfonic acid dimethylamide

{1- [2- (5-Dimethylsulfamoyl-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -carbamic acid tert -butyl ester 84B (129 mg, 0.234 mmol) was dissolved in 1.0 ml of 1,4-dioxane dissolved. To this solution was slowly added 234 μl (0.936 mmol) of a solution of 4.0 M HCl in 1,4-dioxane. Solid formation was noted and the slurry was stirred for 2 hours at room temperature. Diethyl ether was added to the reaction mixture and the crude reaction product was isolated by filtration (141 mg yellow solid). This yellow solid was taken up in DCM and washed once with 10% K ₂ CO ₃ . The organic layer was dried over MgSO ₄ and evaporated under reduced pressure. The resulting yellow solid was purified on silica gel (94 CHCl ₃ : 6 CH ₃ OH: 0.6 NH ₄ OH) to give 10 mg of the title compound 84 as a tan solid.
CI m / z 451 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.81 (s, 1 H), 8.64 (m, 1 H), 8.38 (m, 1 H), 8.34 (s, 1 H), 7 , 88 (m, 1H), 7.71 (m, 1H), 7.52 (m, 2H), 7.29 (m, 1H), 3.89 (m, 1H), 2 , 98 (m, 2H), 2.74 (s, 6H), 2.09 (m, 2H), 1.80 (m, 2H), 1.78 (m, 2H).

Example 85 1- [2- (6-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine

The procedure used for Example 84 was followed except that 5-methoxy-2-nitroaniline was used instead of 4-methoxy-2-nitroaniline in Example 1B to give the title compound 85 as an off-white solid.
CI m / z 374.1 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.60 (s, 1 H), 8.31 (d, J = 8.7 Hz, 1 H), 7.90 (s, 1 H), 7.77 ( d, J = 8.7Hz, 1H), 7.67 (d, J = 8.7Hz, 1H), 7.46 (m, 2H), 7.23 (m, 1H), 7.02 (m, 1H), 3.92 (s, 3H), 3.91 (m, 2H), 2.90 (m, 3H), 2.10 (m, 2H), 1.89 (m, 2H), 1.58 (brs, 2H).

Example 86 1- [2- (5,6-Dimethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine

Example 86A

4,5-dimethoxy-2-nitroaniline

4.50 g (20.0 mmol) of 4,5-dimethoxy-1,2-dinitrobenzene were taken up in a 50.0 ml EtOH / 8.4 ml AcOH mixture. To this was added 4.00 g of powdered iron (0). The reaction mixture was heated overnight to an oil bath temperature of 70 ° C. The reaction mixture was allowed to cool to room temperature and poured into 400 ml H ₂ O. The aqueous layer was extracted several times with diethyl ether. The organic layers were dried over magnesium sulfate and concentrated under reduced pressure Evaporated to give 4.73 g of an orange solid as a mixture of starting material and product. This solid was purified on silica gel (30% DCM in hexanes) to give the title compound 86A as an orange solid (1.15 g, 5.80 mmol).

Example 86B

1- [2- (5,6-Dimethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine

The procedure used for Example 84 was followed, but using 4,5-dimethoxy-2-nitroaniline 86A instead of 4-methoxy-2-nitroaniline in Example 1B to give the title compound 86 as an off-white solid.
CI m / z 374 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.54 (s, 1 H), 8.30 (d, J = 8.7 Hz, 1 H), 7.86 (s, 1 H), 7.64 ( d, J = 8.7 Hz, 1H), 7.45 (m, 1H), 7.33 (s, 1H), 7.30 (m, 1H), 7.20 (m, 1 H), 4.00 (s, 3H), 3.97 (s, 3H), 3.90 (m, 2H), 2.90 (m, 3H), 2.02 (m, 2 H), 1.89 (m, 2 H).

Example 87 2-Dimethylamino-1- (4- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -ethanone

Example 87A

2-chloro-1- (4- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -ethanone

2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -8-piperazin-1-yl-quinoline 63 (215 mg, 0.53 mmol) was dissolved in 2.5 mL of anhydrous DCM under an atmosphere dissolved by dry N ₂ . To this solution was added sequentially 2,6-lutidine (120 μL, 1.06 mmol) and chloroacetyl chloride (630 μL, 0.800 mmol) and the reaction mixture was then stirred at ambient temperature overnight. The reaction mixture was filtered and the solid was collected and dried under vacuum to give 50 mg of the title compound 87A.

Example 87B

2-dimethylamino-1- (4- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -ethanone

2-Chloro-1- (4- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -ethanone 87A (50 mg, 0.10 mmol) was dissolved in 2.0 ml of a 2.0 M solution of dimethylamine in methanol, and the reaction mixture was then stirred for 2 hours at ambient temperature. The reaction mixture was concentrated in vacuo and the residue was purified on flash silica gel eluting with MeOH / DCM (2/98) and then MeOH / DCM / NH ₄ OH (4 / 95.9 / 0.1) and finally MeOH / DCM / NH ₄ OH (6 / 93.9 / 0.1) to give 32.5 mg of the title compound 87.
CI m / z 489 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 8.79 (s, 1 H), 8.49 (d, J = 9.1 Hz, 1 H), 8.24 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 9.1Hz, 1H), 7.48 (m, 1H), 7.39 (m, 1H), 7.17 (m, 2H) , 6.98 (dd, J = 2.5, 9.1Hz, 1H), 4.11 (m, 2H), 3.76 (m, 6H), 3.42 (s, 3H ), 3.14-3.21 (m, 6H), 2.28 (s, 6H).

Example 88 1- [2- (5-Benzyloxy-benzimidazol-1-yl) -quinolin-8-yl] -4-methyl-piperidin-4-ol

Example 88A

1- [2- (5-Benzyloxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-one

2- (5-Benzyloxy-benzimidazol-1-yl) -8-bromo-quinoline (3.46g, 8.05mmol), prepared using the procedure set forth in Example 61, except that 4-benzyloxy-2 -nitrophenylamine was used in place of 5- (2-methoxy-ethoxy) -2-nitro-phenylamine 42A in Example 61D, and 4-piperidone hydrochloride hydrate (2.47 g, 16.1 mmol) was dissolved in ~ 40 ml of 1,4- Dioxane dissolved under an atmosphere of dry N ₂ . To this solution was added Cs ₂ CO ₃ (8.91 g, 27.4 mmol), racemic BINAP (300 mg, 0.482 mmol) and tris (dibenzylideneacetone) dipalladium (0) (147 mg, 0.160 mmol) and the reaction mixture became heated to 100 ° C and reacted overnight at this temperature. The mixture was then cooled to ambient temperature, filtered, and the precipitate was washed several times with DCM / MeOH. The combined filtrates were concentrated in vacuo and the resulting residue was purified via flash silica gel chromatography eluting with MeOH / DCM / NH ₄ OH (1.5 / 98.3 / 0.2) to give 1.91 g of the title compound 88A as an orange solid were obtained.

Example 88B

1- [2- (5-Benzyloxy-benzimidazol-1-yl) -quinolin-8-yl] -4-methyl-piperidin-4-ol

1- [2- (5-Benzyloxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-one 88A (832 mg, 1.85 mmol) was dissolved in 10 mL of anhydrous THF under an atmosphere of dry N ₂ solved. The solution was then cooled to -78 ° C after which 1.2 ml of a 3M solution of methylmagnesium bromide in THF was added. The reaction mixture was warmed to ambient temperature overnight, after which it was quenched with water. The mixture was then concentrated in vacuo and then partitioned between DCM and saturated aqueous NaHCO ₃ . The organic layer was then obtained, washed again with saturated aqueous NaHCO ₃ and then brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a yellow foam. The foam was chromatographed over flash silica gel eluting with MeOH / DCM / NH ₄ OH (1.5 / 98.3 / 0.2) to give 585 mg of the title compound 88 as a yellow solid.
CI m / z 465 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.63 (s, 1 H), 8.35 (d, J = 8.7 Hz, 1 H), 8.23 (d, J = 8.7 Hz, 1 H), 7.60 (d, J = 8.7 Hz, 1H), 7.24-7.48 (m, 9H), 7.10 (dd, J = 2.5, 8.7 Hz , 1H), 5.12 (s, 2H), 3.58 (m, 2H), 3.26 (m, 2H), 2.08 (m, 2H), 1.98 (brs , 1H), 1.84 (m, 2H), 1.37 (s, 3H).

Example 89 (4- {2- [5- (2-Methoxyethoxy) benzimidazol-1-yl] quinolin-8-yl} benzyl) dimethylamine

The procedure used for Example 6 was followed except that trifluoromethanesulfonic acid 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 77E instead of trifluoromethanesulfonic acid-2 - (5-methoxybenzimidazol-1-yl) quinolin-8-yl ester 1E in Example 1F to give the title compound 89.
CI m / z 453 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.57 (s, 1 H), 8.31 (d, J = 9.1 Hz, 1 H), 7.99 (d, J = 9.1 Hz, 1 H), 7.80 (m, 1H), 7.77 (m, 1H), 7.65 (m, 3H), 7.57 (m, 1H), 7.44 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 2.5 Hz, 1H), 6.81 (dd, J = 2.5, 9.1, 1H), 4.15 (m, 2H), 3.77 (m, 2H), 3.56 (s, 2H), 3.45 (s, 3H), 2.33 (s, 6H).

Example 90 (4- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -benzyl) -methylamine

The procedure used for Example 5 was followed except that trifluoromethanesulfonic acid 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 77E instead of trifluoromethanesulfonic acid-2 - (5-methoxybenzimidazol-1-yl) quinolin-8-yl ester 1E in Example 1F to give the title compound 90.
CI m / z 439 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.56 (s, 1 H), 8.31 (d, J = 9.1 Hz, 1 H), 7.94 (d, J = 9.1 Hz, 1 H), 7.80 (m, 1H), 7.75 (m, 1H), 7.63 (m, 3H), 7.56 (m, 1H), 7.43 (d, J = 7.9Hz, 2H), 7.23 (d, J = 2.5Hz, 1H), 6.80 (m, 1H), 4.14 (m, 2H), 3.87 (s, 2H), 3.76 (m, 2H), 3.43 (s, 3H), 2.53 (s, 3H).

Example 91 2- [5- (2-Methoxyethoxy) benzimidazol-1-yl] -8- (4-morpholin-4-ylmethylphenyl) quinoline

The procedure used for Example 5 was followed except that trifluoromethanesulfonic acid 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 77E instead of trifluoromethanesulfonic acid-2 - (5-methoxybenzimidazol-1-yl) quinolin-8-yl ester 1E in Example 1F and morpholine in place of methylamine in Example 5B to give the title compound 91.
CI m / z 495 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.56 (s, 1 H), 8.31 (d, J = 8.7 Hz, 1 H), 7.98 (d, J = 8.7 Hz, 1 H), 7.81 (m, 1H), 7.76 (m, 1H), 7.65 (m, 3H), 7.57 (m, 1H), 7.43 (d, J = 7.9Hz, 2H), 7.25 (d, J = 2.5Hz, 1H), 6.80 (dd, J = 2.5, 9.1, 1H), 4.15 (m, 2H), 3.78 (m, 6H), 3.62 (s, 2H), 3.46 (s, 3H), 2.85 (m, 4H).

Example 92 2- (4- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -benzylamino) -ethanol

The procedure used for Example 5 was followed except that trifluoromethanesulfonic acid 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 77E instead of trifluoromethanesulfonic acid-2 - (5-methoxybenzimidazol-1-yl) quinolin-8-yl ester 1E in Example 1F and ethanolamine instead of methylamine in Example 5B to give the title compound 92.
CI m / z 469 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 8.63 (s, 1 H), 8.14 (d, J = 9.1 Hz, 1 H), 7.71 (d, J = 9.1 Hz, 1 H), 7.68 (dd, J = 2.2, 7.9 Hz, 1 H), 7.59 (d, J = 9.1 Hz, 1 H), 7.54 (dd, J = 2.2, 7.0 Hz, 125 H), 7.43 (m, 1H), 7.35 (d, J = 8.3 Hz, 2H), 7.28 (d, J = B , 3 Hz, 2H), 6.99 (d, J = 2.5 Hz, 1H), 6.50 (m, 1H), 4.00 (m, 2H), 3.83 (s , 2H), 3.70 (m, 4H), 3.41 (s, 3H), 3.21 (m, 2H).

Example 93 4- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -benzylamine

The procedure used for Example 78 was followed except that 4-aminomethylphenylboronic acid hydrochloride was used instead of 2-methoxy-5-pyridineboronic acid and the number of equivalents of potassium phosphate was doubled to give the title compound 93.
CI m / z 425 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 8.69 (s, 1 H), 8.21 (d, J = 9.1 Hz, 1 H), 7.77 (d, J = 8.7 Hz, 1 H), 7.73 (m, 1 H), 7.66 (d, J = 9.1 Hz, 1 H), 7.59 (dd, J = 1.7, 7.0 Hz, 1 H ), 7.48 (m, 1H), 7.41 (d, J = 8.3Hz, 2H), 7.32 (d, J = 8.3Hz, 2H), 7.01 ( d, J = 2.5Hz, 1H), 6.54 (d, J = 2.5, 9.1Hz, 1H), 4.02 (m, 2H), 3.86 (s, 2H), 3.71 (m, 2H), 3.41 (s, 3H).

Example 94 2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -8- (4-pyrrolidin-1-ylmethyl-phenyl) -quinoline

The procedure used for Example 5 was followed except that trifluoromethanesulfonic acid 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 77E instead of trifluoromethanesulfonic acid-2 - (5-methoxybenzimidazol-1-yl) quinolin-8-yl ester 1E in Example 1F and pyrrolidine instead of methylamine in Example 5B to give the title compound 94.
CI m / z 479 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 8.72 (s, 1 H), 8.22 (d, J = 9.1 Hz, 1 H), 7.79 (d, J = 9.1 Hz, 1 H), 7.74 (m, 1 H), 7.69 (d, J = 8.7 Hz, 1 H), 7.57 (dd, J = 1.7, 7.0 Hz, 1 H ), 7.48 (m, 1H), 7.36 (d, J = 8.3Hz, 2H), 7.27 (d, J = 8.3Hz, 2H), 7.03 ( d, J = 2.5 Hz, 1H), 6.50 (m, 1H), 4.02 (m, 2H), 3.70 (m, 2H), 3.65 (s, 2 H), 3.41 (s, 3H), 2.55 (m, 4H), 1.80 (m, 4H).

Example 95 2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -8- (4-pyrrolidin-1-ylmethyl-phenyl) -quinoline

The procedure used for Example 5 was followed except that trifluoromethanesulfonic acid 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 77E instead of trifluoromethanesulfonic acid-2 - (5-methoxybenzimidazol-1-yl) quinolin-8-yl ester 1E in Example 1F and piperidine in place of methylamine in Example 5B to give the title compound 95.
CI m / z 493 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.56 (s, 1 H), 8.30 (d, J = 8.7 Hz, 1 H), 8.00 (d, J = 9.1 Hz, 1 H), 7.78 (dd, J = 1.2, 7.9 Hz, 1H), 7.76 (m, 1H), 7.64 (m, 3H), 7.56 (m, 1 H), 7.45 (d, J = 7.9 Hz, 2 H), 7.25 (d, J = 2.5 Hz, 1 H), 6.81 (d, J = 2.5, 9.1 Hz, 1H, 4.15 (m, 2H), 3.77 (m, 2H), 3.60 (s, 2H), 3.46 (s, 3H), 2, 48 (m, 4H), 1.63 (m, 4H), 1.47 (m, 2H).

Example 96 2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -8- (4-pyrrolidin-1-ylmethyl-phenyl) -quinoline

The procedure used for Example 5 was followed except that trifluoromethanesulfonic acid 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 77E instead of trifluoromethanesulfonic acid-2 - (5-methoxybenzimidazol-1-yl) quinolin-8-yl ester 1E in Example 1F and azetidine in place of methylamine in Example 5B to give the title compound 96.
CI m / z 465 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 8.68 (s, 1H), 8.17 (d, J = 9.1Hz, 1H), 7.72 (d, J = 9.1Hz, 1 H), 7.71 (m, 1 H), 7.62 (d, J = 9.1 Hz, 1 H), 7.54 (dd, J = 1.7, 7.0 Hz, 1 H ), 7.44 (m, 1H), 7.32 (d, J = 7.9Hz, 2H), 7.19 (d, J = 7.9Hz, 2H), 7.02 ( d, J = 2.5 Hz, 1 H), 6.49 (dd, J = 2.5, 9.1 Hz, 1 H), 4.01 (m, 2 H), 3.70 (m, 2H), 3.60 (s, 2H), 3.41 (s, 3H), 3.26 (m, 4H), 2.09 (m, 2H).

Example 97 1- (4- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -benzyl) -cis -pyrrolidine-3,4-diol

The procedure used for Example 5 was followed except that trifluoromethanesulfonic acid 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 77E instead of trifluoromethanesulfonic acid-2 - (5-methoxybenzimidazol-1-yl) quinolin-8-yl ester 1E in Example 1F and cis-pyrrolidine-3,4-diol in place of methylamine in Example 5B to give the title compound 97.
CI m / z 511 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 8.68 (s, 1 H), 8.18 (d, J = 9.1 Hz, 1 H), 7.74 (d, J = 9.1 Hz, 1 H), 7.71 (dd, J = 1.3, 8.3 Hz, 1 H), 7.63 (d, J = 9.1 Hz, 1 H), 7.54 (dd, J = 1.3, 7.0 Hz, 1 H), 7.44 (m, 1 N), 7.33 (d, J = 8.0 Hz, 2 H), 7.25 (d, J = 8, 0 Hz, 2 H), 7.00 (d, J = 2.5 Hz, 1 H), 6.50 (m, 1 H), 4.14 (m, 2 H), 4.01 (m, 2 H), 3.71 (m, 2H), 3.66 (s, 2H), 3.42 (s, 3H), 2.96 (m, 2H), 2.55 (m, 2H).

Example 98 R, R- (1- (4- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -benzyl) -trans-pyrrolidine-3,4 diol)

The procedure used for Example 5 was followed except that trifluoromethanesulfonic acid 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 77E instead of trifluoromethanesulfonic acid-2 - (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl-ester 1E in Example 1F and R, R-trans -pyrrolidine-3,4-diol were used in place of methylamine in Example 5B to give the title compound 98 was obtained.
CI m / z 511 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 8.87 (s, 1 H), 8.40 (d, J = 8.7 Hz, 1 H), 7.96 (d, J = 9.1 Hz, 1 H), 7.88 (m, 2H), 7.71 (dd, J = 1.2, 7.0 Hz, 1H), 7.58 (m, 1H), 7.54 (i.e. , J = 8.3 Hz, 2 H), 7.44 (d, J = 8.3 Hz, 2 H), 7.12 (d, J = 2.5 Hz, 1 H), 6.67 ( dd, J = 2.5, 9.1Hz, 1H), 4.10 (m, 4H), 3.77 (m, 4H), 3.44 (s, 3H), 3.04 (m, 2H), 2.60 (m, 2H).

Example 99 1- (4- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -benzyl) -pyrrolidin-3-ol

The procedure used for Example 5 was followed except that trifluoromethanesulfonic acid 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 77E instead of trifluoromethanesulfonic acid-2 - (5-methoxybenzimidazol-1-yl) quinolin-8-yl ester 1E in Example 1F and racemic 3-pyrrolidinol in place of methylamine in Example 5B to give the title compound 99.
CI m / z 495 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 8.60 (s, 1 H), 8.08 (d, J = 8.7 Hz, 1 H), 7.67 (d, J = 8.7 Hz, 1 H), 7.63 (m, 1 H), 7.53 (d, J = 9.1 Hz, 1 H), 7.49 (dd, J = 1.2, 7.1 Hz, 1 H , 7.39 (m, 1H), 7.39 (d, J = 8.3Hz, 2H), 7.26 (d, J = 8.3Hz, 2H), 6.97 ( d, J = 2.5Hz, 1H), 6.44 (dd, J = 2.5, 9.1Hz, 1H), 4.35 (m, 1H), 3.98 (m, 2H), 3.69 (m, 2H), 3.61 (d, J = 12.5Hz, 1H), 3.57 (d, J = 12.5Hz, 1H), 3, 41 (s, 3H), 2.82 (m, 1H), 2.67 (m, 1H), 2.48 (m, 2H), 2.12 (m, 1H), 1, 70 (m, 1H).

Example 100 R- (1- (4- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -benzyl) -pyrrolidin-3-ol)

The procedure used for Example 5 was followed except that trifluoromethanesulfonic acid 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 77E instead of trifluoromethanesulfonic acid-2 - (5-methoxybenzimidazol-1-yl) quinolin-8-yl ester 1E in Example 1F and R-3-pyrrolidinol were used in place of methylamine in Example 5B to give the title compound 100.
CI m / z 495 [M + 1]; ¹ H NMR (CD ₃ OD) δ 8.69 (s, 1H), 8.19 (d, J = 9.1Hz, 1H), 7.76 (d, J = 9.1Hz, 1 H), 7.71 (m, 1 H), 7.64 (d, J = 8.7 Hz, 1 H), 7.55 (dd, J = 1.3, 7.0 Hz, 1 H ), 7.46 (m, 1H), 7.34 (d, J = 8.3Hz, 2H), 7.27 (d, J = 8.3Hz, 2H), 7.01 ( d, J = 2.5Hz, 1H), 6.49 (dd, J = 2.5, 9.1Hz, 1H), 4.36 (m, 1H), 4.01 (m, 2 H), 3.70 (m, 2 H), 3.67 (d, J = 12.5 Hz, 1 H), 3.62 (d, J = 12.5 Hz, 1 H), 3, 42 (s, 3H), 2.84 (m, 1H), 2.70 (m, 1H), 2.55 (m, 1H), 2.50 (m, 1H), 2, 15 (m, 1H), 1.72 (m, 1H).

Example 101 S- (1- (4- (2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -benzyl) -pyrrolidin-3-ol)

The procedure used for Example 5 was followed except that trifluoromethanesulfonic acid 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 77E instead of trifluoromethanesulfonic acid-2 - (5-methoxybenzimidazol-1-yl) quinolin-8-yl ester 1E in Example 1F and S-3-pyrrolidinol were used in place of methylamine in Example 5B to give the title compound 101.
CI m / z 495 [M + 1]; ¹ H-NMR (C ₃ OD) δ 8.84 (s, 1 H), 8.37 (d, J = 8.7 Hz, 1 H), 7.93 (d, J = 9.1 Hz, 1H), 7.86 (m, 2H), 7.68 (dd, J = 1.7, 7.1Hz, 1H), 7.56 (m, 1H), 7.53 (i.e. , J = 7.9 Hz, 2 H), 7.40 (d, J = 7.9 Hz, 2 H), 7.11 (d, J = 2.5 Hz, 1 H), 6.63 ( dd, J = 2.5, 9.1Hz, 1H), 4.39 (m, 1H), 4.09 (m, 2H), 3.74 (m, 4H), 3.43 (s, 3H), 2.90 (m, 1H), 2.76 (m, 1H), 2.62 (m, 1H), 2.52 (m, 1H), 2.19 (m, 1H), 1.75 (m, 1H).

Example 102 1- (4- {2- [5- (2-Methoxyethoxy) benzimidazol-1-yl] quinolin-8-yl} benzyl) azetidin-3-ol

The procedure used for Example 5 was followed except that trifluoromethanesulfonic acid 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 77E instead of trifluoromethanesulfonic acid-2 - (5-methoxybenzimidazol-1-yl) quinolin-8-yl ester 1E in Example 1F and azetidin-3-ol were used instead of methylamine in Example 5B to give the title compound 102.
CI m / z 481 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 8, 52 (s, 1 H), 8.00 (d, J = 9.1 Hz, 1 H), 7.63 (d, J = 8.7 Hz, 1H), 7.56 (dd, J = 2.3, 7.9Hz, 1H), 7.45 (m, 2H), 7.33 (m, 1H), 7.26 (i.e. , J = 8.3 Hz, 2 H), 7.15 (d, J = 8.3 Hz, 2 H), 6.96 (d, J = 2.5 Hz, 1 H), 6.46 ( dd, J = 2.5, 8.7 Hz, 1H), 4.86 (brs, 1H), 4.37 (m, 1H), 3.96 (m, 2H), 3.68 (m, 2H), 3.63 (s, 2H), 3.59 (m, 2H), 3.40 (s, 3H), 2.98 (m, 2H).

Example 103 2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -8- [4- (4-methylpiperazin-1-ylmethyl) -phenyl] -quinoline

The procedure used for Example 5 was followed except that trifluoromethanesulfonic acid 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 77E instead of trifluoromethanesulfonic acid-2 - (5-methoxybenzimidazol-1-yl) quinolin-8-yl ester 1E in Example 1F and 1-methylpiperazine were used instead of methylamine in Example 5B to give the title compound 103.
CI m / z 508 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.56 (s, 1 H), 8.30 (d, J = 9.1 Hz, 1 H), 7.98 (d, J = 8.7 Hz, 1 H), 7.80 (m, 1H), 7.75 (m, 1H), 7.62 (m, 3H), 7.57 (m, 1H), 7.44 (d, J = 8.3 Hz, 2 H), 7.24 (d, J = 2.1 Hz, 1 H), 6.80 (dd, J = 2.5, 8.7 Hz, 1 H), 4, 15 (m, 2H), 3.77 (m, 2H), 3.62 (s, 2H), 3.45 (s, 3H), 2.70 (m, 8H), 2, 30 (s, 3H).

Example 104 4- (4- {4- [2- (5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -benzyl) -piperazine-1-carboxylic acid tert-butyl ester

The procedure used for Example 5 was followed except that trifluoromethanesulfonic acid 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 77E instead of trifluoromethanesulfonic acid-2 - (5-methoxy-benzimidazol-1-yl) quinolin-8-yl ester 1E in Example 1F and 1-tert-butoxycarbonyl-piperazine were used instead of methylamine in Example 5B to give the title compound 104.
CI m / z 594 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.58 (s, 1 H), 8.35 (d, J = 9.1 Hz, 1 H), 8.00 (d, J = 9.1 Hz, 1 H), 7.82 (m, 1H), 7.78 (m, 1H), 7.67 (m, 3H), 7.60 (m, 1H), 7.47 (d, J = 7.9 Hz, 2 H), 7.26 (d, J = 2.1 Hz, 1 H), 6.83 (dd, J = 2.5, 8.7 Hz, 1 H), 4, 17 (m, 2H), 3.79 (m, 2H), 3.64 (s, 2H), 3.49 (m, 4H), 3.46 (s, 3H), 2, 50 (m, 4H), 1.45 (s, 9H).

Example 105 [1- (4- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -benzyl) -piperidin-4-yl] -carbamic acid tert. butyl ester

The procedure used for Example 5 was followed except that trifluoromethanesulfonic acid 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 77E instead of trifluoromethanesulfonic acid-2 - (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl-ester 1E in Example 1F and 4-N-tert-butoxycarbonyl-aminopiperidine were used in place of methylamine in Example 5B to give the title compound 105.
CI m / z 608 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 8.92 (s, 1 H), 8.48 (d, J = 9.1 Hz, 1 H), 8.04 (d, J = 9.1 Hz, 1H), 7.96 (d, J = 9.1Hz, 1H), 7.92 (m, 1H), 7.75 (m, 1H), 7.61 (m, 3H) , 7.45 (d, J = 7.9 Hz, 2H), 7.16 (d, J = 2.5 Hz, 1H), 6.65 (dd, J = 2.5, 8.7 Hz, 1H), 4.12 (m, 2H), 3.77 (m, 2H), 3.65 (s, 2H), 3.44 (s, 3H), 3.41 ( m, 1H), 3.00 (m, 2H), 2.22 (m, 2H), 1.88 (m, 2H), 1.75 (m, 2H), 1.42 ( s, 9 H).

Example 106 1- (4- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -benzyl) -piperidin-4-ylamine

[1- (4- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -benzyl) -piperidin-4-yl] -carbamic acid tert-butyl ester 105 (110 mg, 0.181 mmol) was dissolved in a solution of 3 ml TFA and 3 ml DCM under an atmosphere of dry N ₂ . The reaction mixture was stirred for 40 min, after which it was concentrated in vacuo, and the residue formed was partitioned between DCM and 1N aqueous NaOH. The DCM layer was then washed again with 1N aqueous NaOH, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 45 mg of the title compound 106.
CI m / z 508 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.55 (s, 1 H), 8.29 (d, J = 8.7 Hz, 1 H), 7.98 (d, J = 9.1 Hz, 1 H), 7.78 (d, J = 8.3 Hz, 1H), 7.76 (m, 1H), 7.60 (m, 4H), 7.42 (d, J = 7, 9Hz, 2H), 7.23 (d, J = 2.5Hz, 1H), 6.80 (m, 1H), 4.14 (m, 2H), 3.76 (m, 2H), 3.59 (s, 2H), 3.44 (s, 3H), 2.93 (m, 2H), 2.68 (m, 1H), 2.11 (m, 2H), 1.94 (brs, 2H), 1.80 (m, 2H), 1.45 (m, 2H).

Example 107 (1- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -methanol

The procedure used for Example 1 was followed except that trifluoromethanesulfonic acid 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 77E instead of trifluoromethanesulfonic acid-2 - (5-methoxybenzimidazol-1-yl) quinolin-8-yl ester 1E and 4- (hydroxymethyl) piperidine in Example 1F and morpholine in place of piperidine-4-yl-carbamic acid tert-butyl ester in Example 1F to give the title compound 107 as a yellow solid.
CI m / z 433 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.66 (s, 1 H), 8.38 (d, J = 9.1 Hz, 1 H), 8.29 (d, J = 9.1 Hz, 1 H), 7.67 (d, J = 8.7Hz, 1H), 7.47 (m, 2H), 7.33 (d, J = 2.5Hz, 1H), 7.28 (m, 1H), 7.10 (dd, J = 2.5, 9.1Hz, 1H), 4.21 (m, 2H), 3.95 (m, 2H), 3, 80 (m, 2H), 3.63 (m, 2H), 3.47 (s, 3H), 2.83 (m, 2H), 1.95 (m, 2H), 1, 5 (m, 3 H).

Example 108 (1- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylmethyl) -methylamine

Example 108A

(1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-carbaldehyde

(1- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -methanol 107 (1.47 g, 3.40 mmol ) was dissolved in 15 ml of anhydrous DCM under an atmosphere of dry N ₂ . To this mixture was added ~2 g of 4Å molecular sieves, 4-methylmorpholine N-oxide (1.19 g, 10.2 mmol), and finally tetrapropylammonium perruthenate (119 mg, 0.340 mmol). The mixture was stirred at ambient temperature overnight, after which it was filtered through Celite ^™ . The Celite ^™ was washed with DCM and the resulting combined filtrate was concentrated in vacuo. The resulting residue was eluted on flash silica gel eluting with a gradient of MeOH / DCM (1/99) to MeOH / DCM (2/98) to give 446 mg of the title compound 108A.

Example 108B

(1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylmethyl) methylamine

(1- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidine-4-carbaldehyde 108A (100 mg, 0.232 mmol) was dissolved in 1 mL of MeOH An atmosphere of dry N _{2 was added} to this solution, 580 μl of a 2.0 M solution of methylamine in MeOH AcOH (~ 100 μl) was added to this solution to a pH of ~ 5, after which NaCNBH ₃ (30 mg, 0.46 mmol) was added to the mixture The reaction mixture was stirred at ambient temperature overnight The reaction mixture was then concentrated under vacuum and partitioned between DCM and 1 N aqueous NaOH. The DCM layer was obtained and washed again with 1 N aqueous NaOH, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was applied to flash silica gel eluting with a gradient of MeOH / DCM (3/97) to MeOH / DCM (5/95) and then a gradient of MeOH / DCM / NH ₄ OH (7 / 92.9 / 0, 1) to MeOH / DCM / NH ₄ OH (9 / 90.9 / 0.1) to give 60 mg of the title compound 108 as a yellow solid.
CI m / z 446 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 8.96 (s, 1 H), 8.68 (d, J = 9.1 Hz, 1 H), 8.44 (d, J = 9.1 Hz, 1 H), 7.93 (d, J = 8.7 Hz, 1 H), 7.57 (d, J = 7.9 Hz, 1 H), 7.49 (m, 1 H), 7, 34 (d, J = 7.9 Hz, 1 H), 7.27 (d, J = 2.5 Hz, 1 H), 7.10 (dd, J = 2.5, 9.1 Hz, 1 H), 4.19 (m, 2H), 3.86 (m, 2H), 3.79 (m, 2H), 3.45 (s, 2H), 2.78 (m, 2 H), 2.63 (m, 2H), 2.45 (s, 3H), 1.92 (m, 2H), 1.68 (m, 3H).

Example 109 2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -8- [4- (4-methylpiperazin-1-ylmethyl) -piperidin-1-yl] -quinoline

The procedure used for Example 108 was followed, but using 1-methylpiperazine instead of methylamine in Example 108B to give the title compound 109.
CI m / z 515 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 8.79 (s, 1 H), 8.48 (d, J = 9.1 Hz, 1 H), 8.19 (d, J = 8.7 Hz, 1 H), 7.67 (d, J = 9.1 Hz, 1 H), 7.38 (m, 2 H), 7.16 (d, J = 2.1 Hz, 1 H), 7, 12 (d, J = 7.4Hz, 1H), 6.90 (m, 1H), 4.11 (m, 2H), 3.75 (m, 2H), 3.63 (m , 2H), 3.43 (s, 3H), 2.20-2.60 (m, 15H), 1.76 (m, 2H), 1.55 (m, 1H), 1 , 45 (m, 2H).

Example 110 (1- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylmethyl) -dimethylamine

The procedure used for Example 108 was followed, but using dimethylamine instead of methylamine in Example 108B to give the title compound 110.
CI m / z 460 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 8.85 (s, 1 H), 8.55 (d, J = 9.1 Hz, 1 H), 8.28 (d, J = 8.7 Hz, 1 H), 7.76 (d, J = 8.7 Hz, 1 H), 7.45 (d, J = 7.9 Hz, 1 H), 7.40 (m, 1 H), 7, 21 (m, 2H), 6.98 (dd, J = 2.1, 9.1Hz, 1H), 4.14 (m, 2H), 3.75 (m, 4H), 3 , 43 (s, 3H), 2.64 (m, 2H), 2.27 (m, 2H), 2.24 (s, 6H), 1.83 (m, 2H), 1 , 63 (m, 1H), 1.54 (m, 2H).

Example 111 1- (1- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylmethyl) -pyrrolidin-3-ol

The procedure used for Example 108 was followed, but using racemic 3-pyrrolidinol in place of methylamine in Example 108B to give the title compound III.
CI m / z 502 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 8.93 (s, 1 H), 8.65 (d, J = 8.7 Hz, 1 H), 8.39 (d, J = 8.7 Hz, 1 H), 7.88 (d, J = 8.7 Hz, 1H), 7.55 (m, 1H), 7.46 (m, 1H), 7.30 (dd, J = 1 , 3, 7.5 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 7.06 (m, 1H), 4.35 (m, 1H), 4 , 18 (m, 2H), 3.78 (m, 4H), 3.45 (s, 3H), 2.86 (m, 1H), 2.74 (m, 3H), 2 , 58 (m, 1, H), 2.50 (m, 3H), 2.12 (m, 1H), 1.93 (m, 2H), 1.60-1.75 (m, 4 H).

Example 112 C- (1- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -methylamine

The procedure used for Example 108 was followed except that ammonium acetate was used instead of methylamine in Example 112 to give the title compound III.
CI m / z 432 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 8.91 (s, 1 H), 8.61 (d, J = 8.7 Hz, 1 H), 8.37 (d, J = 8.7 Hz, 1 H), 7.85 (d, J = 8.7 Hz, 1 H), 7.52 (d, J = 7.1 Hz, 1 H), 7.45 (m, 1 H), 7, 29 (d, J = 7.5 Hz, 1 H), 7.23 (d, J = 2.1 Hz, 1 H), 7.04 (dd, J = 2.5, 9.1 Hz, 1 H), 4.17 (m, 2H), 3.79 (m, 4H), 3.44 (s, 3H), 2.65-2.80 (m, 4H), 1.89 (m, 2H), 1.60 (m, 3H).

Example 113 1- {2- [5- (2-Dimethylamino-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -4-methyl-piperidin-4-ol

Example 113A

1- [8- (4-Hydroxy-4-methyl-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-ol

1- [2- (5-Benzyloxy-benzimidazol-1-yl) -quinolin-8-yl] -4-methyl-piperidin-4-ol 88 (535 mg, 1.15 mmol) was dissolved in 5 mL of anhydrous DCM an atmosphere of dry N ₂ dissolved. The solution was then cooled to 0 ° C, after which 37 μl of NEt ₃ and 150 ml of a 1 M solution of dimethyl bromoborane in DCM were added. The reaction mixture was allowed to warm to ambient temperature and reacted at this temperature for ~ 2 hours. The mixture was then partitioned between isopropanol / DCM (18/82) and saturated aqueous NaHCO ₃ . The aqueous layer was extracted twice more with isopropanol / DCM. The organic extracts were combined, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a yellow solid. The solid was chromatographed over flash silica gel eluting with MeOH / DCM / NH ₄ OH (4 / 95.8 / 0.2) to give 189 mg of the title compound 113A as a yellow solid.

Example 113B

1- {2- [5- (2-Dimethylamino-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -4-methyl-piperidin-4-ol

1- [8- (4-Hydroxy-4-methyl-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-ol 113A (189 mg, 0.505 mmol), Cs ₂ CO ₃ (592 mg, 1.81 mmol), sodium iodide (76 mg, 0.505 mmol) and (2-dimethylamino) ethyl chloride hydrochloride (87 mg, 0.61 mmol) were added to 2 ml of anhydrous DMF and the resulting mixture was heated to 80 ° C under a vacuum Atmosphere heated by dry N ₂ . The reaction was carried out for 48 hours, after which the mixture was cooled to ambient temperature and concentrated in vacuo. The residue was flashed over flash silica gel eluting with gradient from MeOH / DCM (3/97) to MeOH / DCM (8/92) and then switching to MeOH / DCM / NH ₄ OH (8 / 91.8 / 0.2 ) to give 67 mg of the title compound 113 as a yellow oil.
CI m / z 446 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.64 (s, 1 H), 8.33 (d, J = 8.7 Hz, 1 H), 8.29 (d, J = 8.7 Hz, 1 H), 7.66 (d, J = 8.7Hz, 1H), 7.46 (m, 2H), 7.33 (d, J = 2.5Hz, 1H), 7.28 (dd, J = 2.9, 5.8Hz, 1H), 7.08 (dd, J = 2.5, 9.1Hz, 1H), 4.20 (m, 2H), 3 , 60 (m, 2H), 3.26 (m, 2H), 2.86 (m, 2H), 2.41 (s, 6H), 2.10 (m, 2H), 1 , 85 (m, 2H), 1.38 (s, 3H).

Example 114 1- {2- [5- (2-Dimethylamino-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ol

Example 114A

1- [2- (5-Benzyloxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ol

1- [2- (5-Benzyloxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-one 88A (790 mg, 1.76 mmol) was dissolved in 6 mL of MeOH under an atmosphere of dry N ₂ solved. To this solution was added sodium borohydride (66 mg, 1.76 mmol) and the reaction mixture was stirred at ambient temperature overnight. The mixture was then concentrated in vacuo and the resulting residue was partitioned between DCM and 0.1 N aqueous NaOH. The DCM layer was obtained and washed again with 0.1 N aqueous NaOH and then washed twice with brine. The DCM layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a yellow solid. The solid was purified by flash silica gel chromatography eluting with MeOH / DCM / NH ₄ OH (1.5 / 98.3 / 0.2) to give 690 mg of the Ti telverbindung 114A were obtained.

Example 114B

1- [8- (4-Hydroxy-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-ol

1- [2- (5-Benzyloxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ol 114A (440 mg, 0.976 mmol) was suspended in 10 mL of DCE under an atmosphere of dry N ₂ . To this heterogeneous solution was added 5 ml of a 1 M solution of boron tribromide in DCM. The reaction mixture was stirred for 1 h at ambient temperature and then heated to reflux temperature and reacted at this temperature for 2 h. The reaction mixture was then cooled to ambient temperature and added to ice-water. The pH of the resulting reaction mixture was adjusted to 8 by addition of Na ₂ CO ₃ and the solution was extracted five times with isopropanol / DCM (18/82). The organic extracts were combined and dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a yellow solid. The solid was purified by flash silica gel chromatography eluting with MeOH / DCM / NH ₄ OH (3 / 96.8 / 0.2) to give 201 mg of the title compound 114B.

Example 114C

1- {2- [5- (2-Dimethylamino-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ol

1- [8- (4-Hydroxy-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-ol 114B (201 mg, 0.558 mmol), Cs ₂ CO ₃ (400 mg, 1, 22 mmol), sodium iodide (84 mg, 0.559 mmol) and (2-dimethylamino) ethyl chloride hydrochloride (88 mg, 0.62 mmol) were added to 5 ml of anhydrous DMF and the resulting mixture was heated to 65 ° C under an atmosphere of dry N ₂ heated. After 1 h, the reaction temperature was raised to 100 ° C. After reaction at 100 ° C for 1 h, another 44 mg of (2-dimethylamine) ethyl chloride hydrochloride and 200 mg of Cs ₂ CO _{3 were} added. After overnight reaction at 100 ° C, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The resulting residue was partitioned between DCM and aqueous 0.1 N NaOH. The aqueous layer was extracted two more times with DCM and the organic extracts were combined, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a yellow oil. The residue was purified by high pressure liquid chromatography (C-8 reverse phase, linear gradient from 0.1% TFA in water to 0.1% TFA in water / acetonitrile (50/50) over 8 min) to give 43 mg of the title compound 114 as a yellow oil was obtained.
CI m / z 432 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 8.92 (s, 1 H), 8.68 (d, J = 9.1 Hz, 1 H), 8.38 (d, J = 9.1 Hz, 1H), 7.87 (d, J = 9.1Hz, 1H), 7.52 (dd, J = 2.3, 7.9Hz, 1H), 7.45 (m, 1H ), 7.30 (dd, J = 1.2, 7.5 Hz, 1 H), 7.25 (d, J = 2.1 Hz, 1 H), 7.13 (m, 1 H), 4.17 (m, 2H), 3.80 (m, 1H), 3.70 (m, 2H), 2.91 (m, 2H), 2.81 (m, 2H), 2.37 (s, 6H), 2.05 (m, 2H), 1.92 (m, 2H).

Example 115 S, S- (1- (4- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -benzyl) -trans-pyrrolidine-3,4 diol

The procedure used for Example 98 was followed except that S, S-trans-pyrrolidine-3,4-diol was used instead of R, R-trans-pyrrolidine-3,4-diol to give the title compound 115.
CI m / z 511 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 8.95 (s, 1H), 8.49 (d, J = 9.1 Hz, 1 H), 8.04 (d, J = 9.1 Hz, 1H), 7.98 (d, J = 9.1Hz, 1H), 7.94 (m, 1H), 7.761 (m, 1H), 7.65 (m, 1H), 7 , 62 (d, J = 8.3 Hz, 2 H), 7.51 (d, J = 8.3 Hz, 2 H), 7.17 (d, J = 2.5 Hz, 1 H), 6.74 (dd, J = 2.5, 9.1Hz, 1H), 4.13 (m, 4H), 3.88 (dJ = 12.5Hz, 1H), 3.82 (d, J = 12.5Hz, 1H), 3.77 (m, 2H), 3.44 (s, 3H), 3.11 (m, 2H), 2.67 (m, 2H).

Example 116 4- {2- [5- (3-Amino-propoxy) -benzimidazol-1-yl] -quinolin-8-yl} -phenol

Example 116A

Trifluoro-methanesulfonic acid 2- (5-hydroxy-benzimidazol-1-yl) -quinolin-8-yl ester

Trifluoro-methanesulfonic acid 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 77E (2.00 g, 4.28 mmol) was dissolved in 20 ml of anhydrous DCM suspended in an atmosphere of dry N ₂ . To this heterogeneous solution was added 12.9 ml of a solution of 1 M boron tribromide in DCM and the resulting mixture was stirred at ambient temperature for 24 hours. The reaction mixture was then poured into ice-water. The resulting heterogeneous mixture was neutralized by the addition of NaHCO ₃ and then partitioned between isopropanol / DCM (18/82) and aqueous saturated NaHCO ₃ . The organic layer was washed again with aqueous saturated NaHCO ₃ , dried over Na ₂ SO ₄ , filtered, concentrated in vacuo to give 890 mg of a brownish yellow solid as the title compound 116A.

Example 116B

Trifluoro-methanesulfonic acid 2- [5- (3-tert-butoxycarbonyl-amino-propoxy) -benzoimidazol-1-yl] -quinolin-8-yl ester

(3-Hydroxy-propyl) -carbamic acid tert-butyl ester (180 mg, 1.03 mmol) was dissolved in 7 ml of anhydrous THF under an atmosphere of dry N ₂ . Trifluoro-methanesulfonic acid 2- (5-hydroxy-benzimidazol-1-yl) -quinolin-8-yl-ester 116A (420 mg, 1.03 mmol) and triphenylphosphine (538 mg, 2.05 mmol) were added to the solution which resulted in a brown heterogeneous solution. A solution of 320 μl of diethylazodicarboxylate dissolved in 3 ml of anhydrous THF was then added. After ~ 30 min, the reaction mixture was concentrated in vacuo and the residue chromatographed on flash silica gel eluting with MeOH / DCM / NH ₄ OH (1 / 98.8 / 0.2) to give the title compound 116B, 184 mg.

Example 116C

[3- (1- {8- [4- (tetrahydro-pyran-2-yloxy) -phenyl] -quinolin-2-yl} -1H-benzimidazol-5-yloxy) -propyl] -carbamic acid tert-butyl ester

Trifluoro-methanesulfonic acid 2- [5- (3-tert-butoxycarbonyl-amino-propoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 116B (144 mg, 0.254 mmol) was dissolved in 1.0 ml of 1 , 4-dioxane dissolved under an atmosphere of dry N ₂ . To this solution were added 4-hydroxyphenyl boronic acid tetrahydropyranyl ether (67 mg, 0.31 mmol), potassium phosphate (108 mg, 0.508 mmol) and tetrakis (triphenylphosphine) palladium (0) (15 mg, 0.013 mmol). The reaction mixture was heated to 100 ° C and reacted overnight at this temperature in a sealed tube. The reaction mixture was then cooled to ambient temperature, concentrated in vacuo, and the residue was taken up in DCM. The resulting heterogeneous solution was filtered and the filter cake was washed several times with DCM / MeOH (~ 1: 1). The filtrates were combined and concentrated in vacuo and the resulting residue was chromatographed on flash silica gel eluting with MeOH / DCM / NH ₄ OH (1.5 / 98.3 / 0.2) to give 128 mg of the title compound 116C.

Example 116D

4- {2- [5- (3-Amino-propoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -phenol

[3- (1- {8- [4- (Tetrahydropyran-2-yloxy) -phenyl] -quinolin-2-yl} -1H-benzimidazol-5-yloxy) -propyl] -carbamic acid tert -butyl ester 116C (128 mg, 0.215 mmol) was dissolved in 1 ml of TFA under an atmosphere of dry Dissolved N ₂ and then stirred for 10 min. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between isopropanol / DCM (18/82) and aqueous saturated NaHCO ₃ . The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a brown oil. The oil was purified by high pressure liquid chromatography (C-8 reverse phase, linear gradient from 0.01% HCl in water to 0.01% HCl / acetonitrile (over 15 min)) to give 19 mg of the title compound 116 as a white solid. which were further purified by recrystallization from EtOH to give 9 mg of the title compound as the bis-HCl salt.
CI m / z 411 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 9.75 (s, 1 H), 8.61 (d, J = 8.7 Hz, 1 H), 8.19 (d, J = 9.1 Hz, 1 H), 8.03 (d, J = 8.7 Hz, 1 H), 7.95 (m, 1 H), 7.80 (d, J = 6.2 Hz, 1 H), 7, 70 (m, 1H), 7.45 (d, J = 8.3Hz, 2H), 7.30 (m, 1H), 6.95 (m, 1H), 6.94 (i.e. , J = 8.3 Hz, 2H), 4.20 (m, 2H), 3.29 (m, 2H), 2.20 (m, 2H).

Example 117 4- {2- [5- (3-Dimethylminopropoxy) benzimidazol-1-yl] quinolin-8-yl} phenol

The procedure used for Example 4 was followed except that 4- {2- [5- (3-amino-propoxy) -benzimidazol-1-yl] -quinolin-8-yl} -phenol 116 was used instead of 1- [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine 1 to give the title compound 117.
CI m / z 439 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 8.82 (s, 1 H), 8.33 (d, J = 8.7 Hz, 1 H), 7.99 (d, J = 9.1 Hz, 1H), 7.80 (m, 2H), 7.66 (m, 1H), 7.52 (m, 1H), 7.39 (d, J = 8.3Hz, 2H) , 7.07 (d, J = 2.5 Hz, 1H), 6.90 (d, J = 8.3 Hz, 2H), 6.65 (dd, J = 2.5, 9.1 Hz, 1H), 3.99 (m, 2H), 2.75 (m, 2H), 2.46 (s, 6H), 2.00 (m, 2H).

Example 118 1- [2- (5-phenyl-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine

Example 118A

Trifluoro-methanesulfonic acid 1- [8- (4-tert-butoxycarbonylamino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yl ester

{1- [2- (5- (Hydroxybenzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -carbamic acid tert -butyl ester 3A (2.37 g, 5.17 mmol) in 35 mL of anhydrous THF under an atmosphere of dry N ₂ To this solution was added triethylamine (790 μL, 5.68 mmol) and then N-phenyl-bis (trifluoromethanesulfonamide) (2.02 g, 5.68 mmol) The reaction mixture was reacted at this temperature for two days The yellow precipitate was collected by suction filtration, washed with isopropyl ether and dried under vacuum to give the title compound (1.48 g) as a yellow solid.

Example 118B

{1- [2- (5-Phenyl-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -carbamic acid tert-butyl ester

Trifluoromethanesulfonic acid 1- [8- (4-tert-butoxycarbonylamino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yl-ester 118A (150 mg, 0.253 mmol) was prepared in 2 Dissolve 0 ml of 1,4-dioxane under an atmosphere of dry N ₂ . To this solution were added phenylboronic acid (46 mg, 0.38 mmol), potassium phosphate (161 mg, 0.759 mmol) and tetrakis (triphenylphosphine) palladium (0) (15 mg, 0.013 mmol). The reaction mixture was heated to 100 ° C and reacted at this temperature overnight. The reaction mixture was then cooled to ambient temperature, concentrated in vacuo, and the residue was partitioned between DCM and saturated aqueous NaHCO ₃ . The DCM layer was washed again with aqueous saturated NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a yellow oil. The resulting oil was chromatographed on flash silica gel eluting with EtOAc / hexanes (70:30) to give 121 mg of the title compound 118B.

Example 118C

{1- [2- (5-Phenyl-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine

{1- [2- (5-phenyl-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -carbamic acid tert-butyl ester 118B (121 mg, 0.233 mmol) was dissolved in 0.50 TFA was dissolved under an atmosphere of dry N ₂ and then stirred for 45 minutes. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between DCM and aqueous 1N NaOH. The DCM layer was again washed with concentrated under vacuum and the residue formed was partitioned between DCM and aqueous, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a yellow oil as the title compound 118. Compound 118 was dissolved in DCM and then 3 ml of 1 N HCl in ethyl ether was added to the mixture. The precipitate formed was collected by suction filtration and dried under vacuum to give 91 mg of the title compound 118 as the bis-HCl salt.
CI m / z 420 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 10.49 (s, 1 H), 8.84 (d, J = 8.7 Hz, 1 H), 8.80 (d, J = 9.1 Hz, 1H), 8.27 (d, J = 8.7Hz, 1H), 8.16 (m, 2H), 7.91 (m, 1H), 7.80 (m, 4H) , 7.53 (m, 2H), 7.44 (m, 1H), 4.12 (m, 2H), 3.50 (m, 1H), 3.38 (m, 2H) , 2.36 (m, 4H).

Example 119 1- [2- (5-Pyridin-4-yl-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine

The procedure used for Example 118 was followed, but using 4-pyridylboronic acid in place of phenylboronic acid in Step 118B to give the title compound 119 as the free base.
CI m / z 421 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 9.00 (s, 1 H), 8.80 (d, J = 8.5 Hz, 1 H), 8.52 (d, J = 6.0 Hz, 2 H), 8.33 (d, J = 8.7 Hz, 1H), 8.03 (s, 1H), 7.84 (m, 2H), 7.72 (d, J = 6 , 0 Hz, 2H), 7.44 (m, 2H), 7.27 (d, J = 8.5 Hz, 1H), 3.78 (m, 2H), 2.84 (m , 1H), 2.76 (m, 2H), 1.99 (m, 2H), 1.85 (m, 2H).

Example 120 1- {2- [5- (3-Methoxy-phenyl) -benzimidazol-1-yl] -quinolin-8-yl) -piperidin-4-ylamine

The procedure used for Example 118 was followed except that (3-methoxyphenyl) boronic acid was used instead of phenylboronic acid in Step 118B to give the title compound 120 as the free base.
CI m / z 450 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.74 (s, 1 H), 8.46 (d, J = 8.5 Hz, 1 H), 8.30 (d, J = 8.7 Hz, 1 H), 8.08 (d, J = 1.3 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.66 (dd, J = 1.7, 8 , 5 Hz, 1H), 7, 46 (m, 2H), 7.38 (m, 1H), 7.22-28 (m, 3H), 6.90 (m, 1H), 3.89 (m, 2H), 3.87 (s, 3H), 2.90 (m, 3H), 2.05 (m, 2H), 1.83 (m, 2H).

Example 121 1- [2- (5-Pyridin-3-yl-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine

The procedure used for Example 77 was followed except that {1- [2- (5-phenyl-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -carbamic acid tert-butyl ester 118B was used instead of trifluoro-methanesulfonic acid 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 77E in Example 77F was used. The resulting compound was deprotected using the procedure given in Example 118C to give the title compound 121 as the free base.
CI m / z 421 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 9.32 (s, 1 H), 9.27 (s, 1 H), 8.93 (m, 1 H), 8.87 (d, J = 8, 7Hz, 1H), 8.82 (d, J = 5.7Hz, 1H), 8.55 (d, J = 8.9Hz, 1H), 8.24 (s, 1H) , 8.13 (m, 1H), 8.03 (m, 2H), 7.70 (d, J = 8.1 Hz, 1H), 7.57 (m, 1H), 7, 47 (d, J = 7.7 Hz, 1H), 4.01 (m, 2H), 3.38 (m, 1H), 3.05 (m, 2H), 2.13-2 , 24 (m, 4H).

Example 122 1- {2- [5- (6-Methoxy-pyridin-3-yl) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine

The procedure used for Example 118 was followed, but using 2-methoxy-5-pyridinboronic acid instead of phenylboronic acid in Step 118B to give the title compound 122 as the HCl salt.
CI m / z 451 [M + 1]; ¹ H-NMR (DMSO) δ 9.27 (s, 1H), 9.02 (d, J = 8.7 Hz, 1H), 8.61 (d, J = 1.5 Hz, 1H ), 8.57 (d, J = 9.1Hz, 1H), 8.19 (d, J = 8.7Hz, 1H), 8.15 (m, 1H), 8.07 ( s, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1 H), 7.50 (m, 1 H), 7.31 (d, J = 7.5 Hz, 1 H), 6.92 (d, J = 8.3 Hz, 1H), 3.89 (s, 3H), 3.87 (m, 2H), 3.22 (m, 1H), 2.79 (m, 2H), 2.07 (m, 4 H).

Example 123 1- {2- [5- (4-Aminomethyl-phenyl) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine

The procedure used for Example 118 was followed using the HCl salt of 4-aminomethylphenylboronic acid in place of phenylboronic acid in Example 118B and adding 2.5 equivalents of N, N-diisopropylethylamine to the reaction mixture to give the title compound 123 as the HCl. Salt was obtained.
CI m / z 449 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 9.10 (s, 1 H), 8.71 (d, J = 8.7 Hz, 1 H), 8.55 (d, J = 8.7 Hz, 1 H), 8.04 (m, 2H), 7.87 (dd, J = 1.7, 8.7 Hz, 1H), 7.83 (m, 2H), 7.66 (i.e. , J = 7.1 Hz, 1H), 7.58 (m, 3H), 7.40 (m, 1H), 4.18 (s, 2H), 4.03 (m, 2H ), 3.34 (m, 1H), 2.95 (m, 2H), 2.20 (m, 2H), 2.10 (m, 2H).

Example 124 4- {1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yl} -benzoic acid methyl ester

The procedure used for Example 118 was followed, but using 4-methoxycarbonylphenylboronic acid instead of phenylboronic acid in Step 118B to give the title compound 124 as the HCl salt.
CI m / z 478 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 9.08 (s, 1 H), 8.79 (d, J = 8.7 Hz, 1 H), 8.52 (d, J = 8.7 Hz, 1 H), 8.11 (m, 2 H), 8.07 (d, J = 1.3 Hz, 1 H), 8.02 (d, J = 9.1 Hz, 1 H), 7, 87 (m, 1H), 7.83 (m, 2H), 7.65 (m, 1H), 7.55 (m, 1H), 7.39 (m, 1H), 4, 03 (m, 2H), 3.93 (s, 3H), 3.33 (m, 1H), 2.93 (m, 2H), 2.19 (m, 2H), 2, 11 (m, 2H).

Example 125 4- {1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yl} -phenol

The procedure used for Example 118 was followed except that 4-hydroxyphenylboronic acid Re-tetrahydropyranyl ether was used in place of phenylboronic acid in step 118B to give the title compound 125 as the HCl salt.
CI m / z 436 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 9.20 (s, 1 H), 8.72 (d, J = 8.3 Hz, 1 H), 8.49 (d, J = 8.7 Hz, 1 H), 7.98 (d, J = 8.7 Hz, 1H), 7.90 (s, 1H), 7.79 (m, 1H), 7.64 (d, J = 7 , 5Hz, 1H), 7.53 (m, 3H), 7.39 (d, J = 7.9Hz, 1H), 6.88 (m, 2H), 4.03 (m , 2H), 3.34 (m, 1H), 2.93 (m, 2H), 2.19 (m, 2H), 2.10 (m, 2H).

Example 126 2- (5-Methoxy-benzimidazol-1-yl) quinoline-8-carboxylic acid methyl ester

Trifluoromethanesulfonic acid 2- (5-methoxybenzimidazol-1-yl) quinolin-8-yl ester 1E (1.0 g, 2.3 mmol), palladium acetate (16 mg, 0.07 mmol), 1 , 3-Bis (diphenylphosphine) propane (30 mg, 0.07 mmol) and triethylamine (730 μL, 5.20 mmol) were dissolved in a solution of 8 mL DMF and 4 mL MeOH in a Parr bottle. The reaction vessel was evacuated under vacuum and then filled with carbon monoxide (50 psi). The reaction mixture was shaken for 24 h at which time it was concentrated in vacuo. The resulting residue was partitioned between DCM and aqueous saturated NaHCO ₃ . The DCM layer was then washed again with aqueous saturated NaHCO ₃ and then with brine, dried, filtered over Na ₂ SO ₄ and concentrated under vacuum to give a light tan foam. The foam was chromatographed on flash silica gel eluting with MeOH / DCM (1:99) to give 770 mg of the title compound 126.
CI m / z 334 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.63 (d, J = 8.9 Hz, 1 H), 8.56 (s, 1 H), 8.25 (d, J = 8.9 Hz, 1 H), 8.10 (dd, J = 1.5, 7.2 Hz, 1H), 7.90 (dd, J = 1.5, 8.1 Hz, 1H), 7.64 (i.e. , J = 8.9 Hz, 1H), 7.51 (m, 1H), 7.27 (d, J = 2.5 Hz, 1H), 7.07 (dd, J = 2.5 , 9.1 Hz, 1H), 4.04 (s, 3H), 3.87 (s, 3H).

Example 127 Methyl 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinoline-8-carboxylate

The procedure used for Example 126 was followed except that trifluoromethanesulfonic acid 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl-ester 77E instead of trifluoromethanesulfonic acid-2 - (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl-ester 1E to give the title compound 127 as a white solid.
CI m / z 378 [M + 1]; ¹ H-NMR (DMSO) δ 9.17 (s, 1H), 8.73 (d, J = 9.1Hz, 1H), 8.64 (d, J = 9.1Hz, 1H ), 8.23 (d, J = 8.7 Hz, 1H), 8.18 (m, 1H), 8.05 (m, 1H), 7.64 (m, 1H), 7 , 29 (d, J = 2.5Hz, 1H), 7.07 (dd, J = 2.5, 9.1Hz, 1H), 4.14 (m, 2H), 4.00 (s, 3H), 3.67 (m, 2H), 3.31 (s, 3H).

Example 128 2- (5-Methoxy-benzimidazol-1-yl) -quinoline-8-carboxylic acid (2-dimethylamino-ethyl) -amide

Methyl 2- (5-methoxy-benzimidazol-1-yl) -quinoline-8-carboxylate 126 (166.7 mg, 0.500 mmol) was dissolved in 2 mL of anhydrous DCM under an atmosphere of dry N ₂ . In a separate flask, N, N-dimethylethylenediamine (2.20 ml, 20 mmol) was dissolved in 20 ml of anhydrous DCM under an atmosphere of dry N ₂ . To this solution was added slowly 10 m of a solution of 2.0 M trimethylaluminum in toluene. The solution was stirred for 30 minutes, after which 1 ml of this solution was added to the solution containing compound 126. The temperature of the reaction mixture was raised to 40 ° C and allowed to react overnight, after which 1 ml of water was slowly added to quench the reaction. The resulting mixture was partitioned between DCM and aqueous 0.1 N NaOH. The DCM layer was washed again with aqueous 0.1N NaOH and then with brine. The DCM layer was then dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was dissolved in 2 ml of DCM. To this solution was added 1.5 ml of a solution of HCl in ethyl ether which caused the formation of an immediate precipitate. The precipitate was collected by suction filtration, washed with ethyl ether and dried under vacuum to give 154 mg of the bis-HCl salt of the title compound 128 as a white solid.
CI m / z 390 [M + 1]; ¹ H-NMR (CD ₃ OD) 10.22 (s, 1H), 8.85 (d, J = 8.9 Hz, 1H), 8.54 (d, J = 9.0 Hz, 1 H), 8.49 (dd, J = 1.5, 7.2 Hz, 1H), 8.30 (dd, J = 1.4, 8.1 Hz, 1H), 8.18 (i.e. , J = 8.9 Hz, 1H), 7.86 (m, 1H), 7.42 (m, 2H), 3.97 (s, 3H), 3.90 (m, 2H ), 3.44 (m, 2H), 2.96 (s, 6H).

Example 129 2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) quinoline-8-carboxylic acid methyl ester

The procedure used for Example 126 was followed, but using 4-cyclopropylmethoxy-2-nitro-phenylamine 52A instead of 4-methoxy-2-nitroaniline in Example 1B to give the title compound 129.
CI m / z 374 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.65 (d, J = 9.1 Hz, 1 H), 8.60 (s, 1 H), 8.34 (d, J = 8.7 Hz, 1 H), 8.14 (m, 1H), 7.97 (m, 1H), 7.72 (d, J = 9.1Hz, 1H), 7.57 (m, 1H), 7.29 (d, J = 2.5Hz, 1H), 7.10 (m, 1H), 4.09 (s, 3H), 3.89 (d, J = 7.1Hz, 2H), 1.32 (m, 1H), 0.66 (m, 2H), 0.38 (m, 2H).

Example 130 [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -pyrrolidin-1-yl-methanone

The procedure used for Example 128 was followed except that 2- (5-cyclopropylmethoxy-benzimidazol-1-yl) -quinoline-8-carboxylic acid methyl ester 129 was used instead of 2- (5-methoxy-benzimidazol-1-yl) -quinoline 8-carboxylic acid methyl ester 126 and pyrrolidine were used in place of N, N-dimethylethylenediamine to afford the title compound 130 as a white solid.
CI m / z 413 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.58 (s, 1 H), 8.51 (d, J = 9.1 Hz, 1 H), 8.26 (d, J = 9.1 Hz, 1 H), 7.80 (d, J = 7.9 Hz, 1 H), 7.76 (d, J = 7.1 Hz, 1 H), 7.67 (d, J = 8.7 Hz, 1H), 7.52 (m, 1H), 7.25 (d, J = 2.1Hz, 1H), 7.07 (m, 1H), 3.92 (m, 1H) , 3.88 (d, J = 7.1 Hz, 2H), 3.85 (m, 1H), 3.19 (m, 1H), 3.10 (m, 1H), 1, 95 (m, 2H), 1.75 (m, 2H), 1.32 (m, 1H), 0.67 (m, 2H), 0.39 (m, 2H).

Example 131 [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -morpholin-4-yl-methanone

The procedure used for Example 128 was followed except that 2- (5-cyclopropylmethoxy-benzimidazol-1-yl) -quinoline-8-carboxylic acid methyl ester 129 was used instead of 2- (5-methoxy-benzimidazol-1-yl) -quinoline 8-carboxylic acid methyl ester 126 and morpholine were used in place of N, N-dimethylethylenediamine to afford the title compound 131 as a white solid.
CI m / z 429 [M + 1].

Example 132 [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-1-yl-methanone

The procedure used for Example 128 was followed except that 2- (5-cyclopropylmethoxy-benzimidazol-1-yl) -quinoline-8-carboxylic acid methyl ester 129 was used instead of 2- (5-methoxy-benzimidazol-1-yl) -quinoline 8-carboxylic acid methyl ester 126 and piperidine were used in place of N, N-dimethylethylenediamine to afford the title compound 132 as a yellow solid.
CI m / z 427 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.61 (s, 1 H), 8.49 (d, J = 9.1 Hz, 1 H), 8.31 (d, J = 9.1 Hz, 1 H), 7.85 (d, J = 7.9 Hz, 1H), 7.72 (m, 2H), 7.56 (m, 1H), 7.29 (d, J = 2, 5Hz, 1H), 7.09 (m, 1H), 4.09 (m, 1H), 3.88 (d, J = 6.7Hz, 2H), 3.78 (m, 1H), 3.13 (m, 2H), 1.20-1.80 (m, 7H), 0.66 (m, 2H), 0.39 (m, 2H).

Example 133 (3-Amino-pyrrolidin-1-yl) - [2- (5-cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -methanone

Example 133A

4-cyclopropylmethoxy-2-nitro-phenylamine

4-Amino-3-nitrophenol (26.00 g, 165.5 mmol) was dissolved in 200 mL of anhydrous DMF under an atmosphere of dry N ₂ . The reaction mixture was then cooled to 0 ° C and to this mixture was added Cs ₂ CO ₃ (64.7 g, 199 mmol) and cyclopropylmethane bromide (17.7 mL, 182 mmol). After stirring for 15 min, the reaction mixture was then warmed to ambient temperature and then stirred overnight. The reaction mixture is then poured into 100 ml of water. The precipitate was collected by suction filtration and partitioned between DCM and aqueous 0.1 N NaOH. The DCM layer was obtained and washed again with aqueous 0.1 N NaOH, then brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 31.52 g of 4-cyclopropylmethoxy-2-nitro-phenylamine 133A were obtained as an orange solid.

Example 133B

{1- [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-carbonyl] -pyrrolidin-3-yl} -carbamic acid tert-butyl ester

Trifluoromethanesulfonic acid 2- (5-cyclopropylmethoxybenzimidazol-1-yl) quinolin-8-yl ester (602 mg, 1.30 mmol) (prepared according to Example 77E except that 4-cyclopropylmethoxy-2- nitro-phenylamine 133A was used instead of 5- (2-methoxyethoxy) -2-nitro-phenylamine 42A in Example 77C), palladium acetate (9.0 mg, 0.04 mmol), 1,3-bis (diphenylphosphio) Propane (16 mg, 0.04 mmol), (+/-) - 3- (tert-butoxycarbonylamino) pyrrolidine (484 mg, 2.60 mmol) and triethylamine (400 μL, 2.86 mmol) were dissolved in 6 mL of DMF and 4 ml of MeOH dissolved in a Parr bottle. The reaction vessel was evacuated under vacuum and then filled with carbon monoxide (50 psi). The reaction mixture was shaken for 24 h at which time it was concentrated in vacuo. The resulting residue was partitioned between DCM and aqueous saturated NaHCO ₃ . The DCM layer was then washed again with aqueous saturated NaHCO ₃ and then brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The resulting residue was chromatographed on flash silica gel eluting with MeOH / DCM (1:99) to give 139 mg of the title compound 133B.

Example 133C

(3-Amino-pyrrolodin-1-yl) - [2- (5-cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -methanone

{1- [2- (5-Cyclopropylmethoxybenzimidazol-1-yl) quinoline-8-carbonyl] -pyrrolidin-3-yl} -carbamic acid tert -butyl ester 133B (130 mg, 0.246 mmol) was dissolved in a solution of Dissolve 1 ml TFA and 1 ml DCM under an atmosphere of dry N ₂ . The reaction mixture was stirred for 30 minutes. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between DCM and aqueous 1N NaOH. The DCM layer was washed again, concentrated in vacuo and the resulting residue was partitioned between DCM and aqueous, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound 133. CI m / z 428 [M + 1].

Example 134 8-Allyloxy-2- (5-methoxybenzimidazol-1-yl) quinoline

2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-ol 1D (292 mg, 1.00 mmol) was dissolved in 5 mL of anhydrous THF under an atmosphere of dry N ₂ and the reaction mixture was brought to 0 ° C cooled. To this solution was slowly added 60% sodium hydride in oil (44 mg, 1.1 mmol). After reaction for 30 min, allyl bromide (100 μl, 1.1 mmol) was added and the reaction mixture was then warmed to ambient temperature and treated with 1 ml of DMF. After stirring overnight at ambient temperature, the reaction mixture was partitioned between DCM and aqueous saturated NaHCO ₃ . The DCM layer was washed again with aqueous saturated NaHCO ₃ , then washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a red solid. The red solid was chromatographed over flash silica gel, eluting with EtOAc, to give 245 mg of the title compound 134 as a tan solid.
CI m / z 332 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.60 (d, J = 8.9 Hz, 1 H), 8.57 (s, 1 H), 8.19 (d, J = 8.7 Hz, 1 H), 7.59 (d, J = 8.7Hz, 1H), 7.37 (m, 2H), 7.30 (d, J = 2.5Hz, 1H), 7.07 (dd, J = 1.9, 7.0 Hz, 1H), 7.02 (dd, J = 2.5, 9.1 Hz, 1H), 6.21 (m, 1H), 5 , 62 (m, 1H), 5.36 (m, 1H), 4.76 (m, 2H), 3.87 (s, 3H).

Example 135 {2- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yloxy] -ethyl} -methyl-amine

Example 135A

[2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yloxy] -acetaldehyde

8-Allyloxy-2- (5-methoxy-benzimidazol-1-yl) -quinoline 134 (245 mg, 0.74 mmol) and trimethylamine N-oxide dihydrate (101 mg, 0.88 mmol) were added in 3 mL anhydrous DCM under an atmosphere of dry N ₂ dissolved. To this solution was added osmium tetroxide (245 mg, 0.74 mmol) and the reaction mixture was stirred for ~ 1 h at ambient temperature. The reaction mixture was then concentrated in vacuo and the resulting residue was dissolved in 2 ml of THF. To this solution was added 2 ml of water followed by sodium periodate (238 mg, 1.11 mmol) and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was partitioned between DCM and aqueous saturated NaHCO ₃ , causing the formation of a precipitate. The brown solid was collected by suction filtration and dried under vacuum to give 214 mg of the title compound 135A.

Example 135B

{2- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yloxy] -ethyl} -methyl-amine

[2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yloxy] -acetaldehyde 135A (214 mg, 0.64 mmol), 400 μl AcOH, 1.6 ml of a solution of 2M methylamine in MeOH and Na (OAc) ₃ BH (204 mg, 0.96 mmol) were added to 3 ml of DCE under an atmosphere of dry N ₂ . The reaction mixture was stirred overnight at ambient temperature, after which it was partitioned between DCM and aqueous 1N NaOH. The DCM layer was washed two more times with aqueous 1N NaOH, then with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was purified on flash silica gel eluting with first MeOH / EtOAc (4/96), then MeOH / EtOAc / NH ₄ OH (8 / 91.9 / 0.1), then MeOH / EtOAc / NH ₄ OH (10 / 89.9 / 0.1) and finally MeOH / EtOAC / NH ₄ OH (15 / 84.9 / 0.1), where at 28 mg of the title compound 135 was obtained as a white solid.
CI m / z 349 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.63 (d, J = 9.1 Hz, 1 H), 8.60 (s, 1 H), 8.27 (d, J = 8.7 Hz, 1 H), 7.66 (d, J = 8.9Hz, 1H), 7.43 (m, 2H), 7.33 (d, J = 2.5Hz, 1H), 7.14 (dd, J = 2.1, 6.9 Hz, 1H), 7.05 (dd, J = 2.5, 8.9 Hz, 1H), 4.35 (m, 2H), 3 , 89 (s, 3H), 3.21 (m, 2H), 2.61 (s, 3H), 2.02 (brs, 1H).

Example 136 {2- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yloxy] -ethyl} -dimethyl-amine

{2- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yloxy] -ethyl} -methyl-amine 135 (23 mg, 0.066 mmol), 20 μl of 37% formaldehyde in water and 20 μl of formic acid was added to 500 μl of chloroform under an atmosphere of dry N ₂ . The reaction mixture was then heated to reflux for ~2 hours after which time it was concentrated in vacuo and partitioned between DCM and aqueous 1N NaOH. The DCM layer was washed again with aqueous 1N NaOH then brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 20 mg of the title compound 136.
CI m / z 363 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.67 (d, J = 9.1 Hz, 1 H), 8.61 (s, 1 H), 8.28 (d, J = 8.7 Hz, 1 H), 7.67 (d, J = 8.9Hz, 1H), 7.43 (m, 2H), 7.32 (d, J = 2.3Hz, 1H), 7.13 (d, J = 7.3Hz, 1H), 7.06 (dd, J = 2.5, 8.9Hz, 1H), 4.34 (m, 2H), 3.90 (s , 3H), 3.00 (m, 2H), 2.46 (s, 6H).

Example 137 2- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yloxy] -ethyl} -amine

2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-ol 1D (290 mg, 0.996 mmol) was dissolved in 5 ml of anhydrous DMF under an atmosphere of dry N ₂ . To this solution was added slowly 60% sodium hydride in oil (44.1 mg, 1.10 mmol). After reaction for 30 minutes, N- (2-bromoethyl) phthalimide (280 mg, 1.10 mmol) was added and the reaction mixture was then heated to 80 ° C. After stirring for 2 h at this temperature, K ₂ CO ₃ (360 mg, 2.61 mmol) was added and the reaction was stirred at 80 ° C overnight. The reaction mixture was then cooled to ambient temperature and partitioned between EtOAc and water. The EtOAC layer was then washed four more times with water, then with brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was chromatographed over flash silica gel eluting with a gradient of DCM / Hex (50/50) to DCM and then to MeOH / DCM (2/98) to give a white solid. The white solid was dissolved in 5 mL of hot EtOH (reflux), to which was added 500 μL of anhydrous hydrazine. After reacting with refluxing for 2 h, the reaction mixture was cooled to ambient temperature, filtered, and the filter cake was washed with EtOH. The combined filtrates were concentrated in vacuo and the resulting residue was switched over flash silica gel eluting with a gradient of DCM to MeOH / DCM (8/92), then to MeOH / NH ₄ OH (8 / 91.9 / 0.1) , chromatographed to give 110 mg of the title compound 137 as a white solid.
¹ H-NMR _(CDCl3) δ 8.60 (d, J = 8.9 Hz, 1 H), 8.58 (d, J = 8.9 Hz, 1 H), 8.57 (s, 1 H), 8.21 (d, J = 8.7 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.39 (m, 2H), 7.29 (d, J = 2.5Hz, 1H), 7.08 (dd, J = 1.9, 7.1Hz, 1H), 7.03 (dd, J = 2.5, 8.9 Hz, 1H), 4.21 (m, 2H), 3.86 (s, 3H), 3.27 (m, 2H), 2.26 (brs, 2H).

Example 138 1 - [[2- [5- (3-morpholinoethoxy) -1H-benzimidazol-1-yl] quinolin-8-yl]] - piperidin-4-ylamine trihydrochloride

Example 138A, B

8-chloro-2- (5-methoxy-1H-benzimidazol-1-yl) quinoline and 8-chloro-2- (6-methoxy-1H-benzimidazol-1-yl) -quinoline

2,8-Dichloroquinoline (11.89 g, 60 mmol), sodium hydride (60% dispersion in mineral oil, 2.88 g, 72 mmol) and 50 mL of toluene were combined under nitrogen and a solution containing 5-methoxybenzimidazole (10 , 67 g, 72 mmol) dissolved in 100 ml of anhydrous 1-methyl-2-pyrrolidinone was added carefully by syringe. The resulting mixture was slowly warmed to 110 ° C and stirred at this temperature for 16 h. After cooling, the reaction mixture was quenched with 650 ml of water and then extracted several times with EtOAc. The combined EtOAC extracts were dried over Na ₂ SO ₄ and evaporated to leave a semi-solid residue containing title product isomers 138A, B. A ¹ H NMR spectrum of this product mixture revealed that the formation of the 6-methoxybenzimidazol-1-yl isomer was favored over the 5-methoxybenzimidazol-1-yl isomer at a ratio of about 3: 2. Fractional crystallization from EtOH gave three early crystalline batches which were combined to give 7.34 g consisting of about 90% pure 6-methoxybenzimidazol-1-yl isomer. Recrystallization from EtOH yielded needle-like crystals of the 6-methoxybenzimidazol-1-yl isomer 138A which melts at 175-176 ° C.
CI m / z 310 [M + 1]; ¹ H NMR (DMSO) δ 9.18 (s, 1H), 8.77 (d, J = 2.5Hz, 1H), 8.65 (d, J = 9.0Hz, 1H ), 8.30 (d, J = 9.0 Hz, 1H), 8.01 (m, 2H), 7.68 (d, 8.7 Hz, 1H), 7.58 (m, 1 H), 7.00 (dd, J = 2.5, 8.7 Hz, 1 H), 3.92 (s, 3 H).

Further fractional crystallization efforts ultimately yielded two batches of a combined weight of 2.157 g of the 5-methoxybenzimidazol-1-yl isomer 138B, which melts at 184-185 ° C.
¹ H-NMR (DMSO) δ 9.27 (s, 1H), 8.98 (d, J = 9.0 Hz, 1H), 8.67 (d, J = 9.0 Hz, 1H ), 8.31 (d, J = 9.0 Hz, 1H), 8.02 (m, 2H), 7.59 (m, 1H), 7.35 (d, J = 2.2 Hz, 1 H), 7.12 (dd, J = 2.2, 9.0 Hz, 301 H), 3.87 (s, 3 H).

Example 138C

8-chloro-2- (5-hydroxy-1H-benzimidazol-1-yl) quinoline

To a pre-cooled (-73 ° C) solution containing 8-chloro-2- (5-methoxy-1H-benzimidazol-1-yl) quinoline 138B (2.16 g, 7.0 mmol) in anhydrous DCM (28 ml), a 1.0 M solution of boron tribromide in DCM (20.9 mL, 20.9 mmol) was added. The cooling bath was removed and the reaction mixture was stirred at ambient temperature under nitrogen for 22 h. The reaction mixture was quenched to a pH of about 8.8 by the addition of aqueous 1N NaOH. After stirring for about 15 minutes, the suspended solids were removed by filtration. The solids were then stirred briefly with 1N NaOH (21 mL, 21 mmol) to hydrolyze remaining borate esters and then neutralized by the addition of 1N HCl (21 mL, 21 mmol). The solid precipitate was filtered off, stirred briefly with a small amount of warm EtOAC to remove traces of starting material and refiltered to give 1.91 g, m.p.> 250 ° C, of the title product 1380.
CI m / z 296 [M + 1]; ¹ H-NMR (DMSO) δ 9.41 (br, s, 1H), 9.20 (s, 1H), 8.86 (d, J = 9.1Hz, 1H), 8.65 (d, J = 9.1Hz, 1H), 8.28 (d, J = 8.7Hz, 1H), 8.00 (d, J = 7.9Hz, 2H), 7, 57 (t, J = 7.9 Hz, 1 H), 7.08 (d, J = 2.5 Hz, 1 H), 6.93 (dd, J = 2.5, 8.7 Hz, 1 H):

Example 138D

8-chloro-2- [5- (3-morpholinopropoxy) -1H-benzimidazol-1-yl) quinoline

8-Chloro-2- (5-hydroxy-1H-benzimidazol-1-yl) quinoline 138C (0.30 g, 1 mmol) and NaOH (0.047 g of a 60% dispersion in mineral oil, 1.1 mmol) with 3 ml of anhydrous DMF under argon and the mixture was allowed to react for 1 h at ambient temperature. To this was added 4- (3-chloropropyl) morpholine (0.199 g, 1.22 mmol) and the reaction mixture was stirred at ambient temperature for 4 days. Any remaining sodium hydride was quenched by the addition of water and the solvents were evaporated in vacuo. Water (3 ml) was added to the residue and the residue was extracted with chloroform (5 x 20 ml). The combined chloroform extracts were dried over Na ₂ SO ₄ and evaporated to give an off-white solid. The solids were stirred with a small amount of EtOH and filtered to give 0.157 g of the title product 138D.
CI m / z 423 [M + 1]; ¹ H NMR (DMSO) δ 9.24 (s, 1H), 8.95 (d, J = 9.1Hz, 1H), 8.66 (d, J = 9.1Hz, 1H ), 8.30 (d, J = 9.1 Hz, 1 H), 8.01 (d, J = 7.9 Hz, 2 H), 7.57 (t, J = 7.9 Hz, 1 H), 7.30 (d, 35 J = 2.1 Hz, 1 H), 7.08 (dd, J = 2.5, 9.1 Hz, 1 H), 4.08 (t, J = 6.4Hz, 2H), 3.56 (m, 4H), 2.43 (t, J = 7.3Hz, 2H), 2.36 (m, 4H), 1.89 ( m, 2 H).

Example 138E

{1 - [[2- [5- (3-morpholinopropoxy) -1H-benzimidazol-1-yl] -quinolin-8-yl]) - piperidin-4-yl} -carbamic acid tert-butyl ester

8-Chloro-2- [5- (3-morpholinopropoxy) -1H-benzimidazol-1-yl) quinoline 138D (226 mg, 0.53 mmol), racemic BINAP (50 mg, 0.08 mmol), Cs ₂ CO ₃ (243 mg, 0.75 mmol), tert-butyl piperidin-4-ylcarbamate (214 mg, 1.07 mmol), xylenes (1 mL) and Pd (OAc) ₂ (12 mg, 0.053 mmol ) were combined under argon and heated under reflux for two days. After allowing the mixture to cool, hexanes were added and decanted several times to remove hexane solubles. The residue was stirred with EtOAc, filtered, and the solids were washed with more EtOAc. The combined EtOAC solutions were evaporated and the residue was chromatographed on silica gel with EtOAC / MeOH elution. The fractions containing title product 138E were combined and concentrated to give 130 mg.
CI m / z 587 [M + 1]; ¹ H-NMR (DMSO) δ 9.15 (s, 1H), 8.88 (d, J = 9.6Hz, 1H), 8.51 (d, J = 8.7Hz, 1H ), 8.14 (d, J = 9.1 Hz, 1 H), 7.59 (d, J = 7.0 Hz, 1 H), 7.46 (t, J = 7.9 Hz, 1 H), 7.30 (m, 3H), 7.13 (d, J = 8.3Hz, 1H), 4.08 (t, J = 6.2Hz, 2H), 3.75 (m, 2H), 3.56 (m, 4H), 3.42 (m, 1H), 2.74 (t, J = 10.8Hz, 2H), 2.44 (m, 2H), 2.36 (m, 4H), 1.8-1.9 (m, 6H), 1.39 (s, 9H).

Example 138F

1 - [[2- [5- (3-morpholinopropoxy) -1H-benzimidazol-1-yl] -quinolin-8-yl]] - piperidin-4-ylamine trihydrochloride

{1- [[2- [5- (3-morpholinopropoxy) -1H-benzimidazol-1-yl] -quinolin-8-yl]] - piperidin-4-yl} -carbamic acid tert-butyl ester 138E (98 mg, 0.17 mmol) was stirred at ambient temperature with 4 N HCl in dioxane (0.5 mL, 2 mmol). After 4 h, the mixture was rotary evaporated to give the title product 138 as a pale yellow solid.
CI m / z 487 [M + 1]; ¹ H-NMR (DMSO) δ 9.55 (brs, 1H), 8.94 (d, J = 8.7 Hz, 1H), 8.65 (d, J = 9.0 Hz, 1H ), 8.4 (brs, 3H), 8.24 (d, J = 9, 0Hz, 1H), 7.72 (d, J = 8.1Hz, 1H), 7.58 ( m, 2H), 7.42 (m, 2H), 4.24 (t, J = 5.6Hz, 2H), 4.0 (m, 2H), 3.9 (m, 4 H), 3.5 (m, 2H), 3.3 (m, 3H), 3.1 (m, 2H), 2.88 (m, 2H), 2.29 (m, 2 H), 2.12 (m, 4H).

Example 139 1 - [[2- [5- (3-morpholinoethoxy) -1H-benzimidazol-1-yl] quinolin-8-yl]] - piperidin-4-ylamine trihydrochloride

Example 139A

8-chloro-2- [5- (3-morpholinoethoxy) -1H-benzimidazol-1-yl] quinoline

8-Chloro-2- (5-hydroxy-1H-benzimidazol-1-yl) quinoline 138B (296 mg, 1 mmol) and Cs ₂ CO ₃ (717 mg, 2.2 mmol) and 3 mL of anhydrous dioxane were combined and heated at 80 ° C under nitrogen for 1.5 h. Morpholinoethyl chloride hydrochloride (223 mg, 1.2 mmol) was added and heating was continued at 80 ° C overnight. Additional morpholinoethyl chloride hydrochloride (112 mg, 0.6 mmol) and Cs ₂ CO ₃ (358 mg, 1.1 mmol) were added and the mixture was heated for a further two days. After evaporation of the solvent, water (2 ml) was added to the residue and the mixture extracted with EtOAc. The EtOAC extract was dried over Na ₂ SO ₄ and evaporated to give 200 mg of the title product 139A as an off-white solid

Example 139B

{1 - [[2- [5- (3-morpholinoethoxy) -1H-benzimidazol-1-yl] -quinolin-8-yl]] - piperidin-4-yl} -carbamic acid tert-butyl ester

8-Chloro-2- [5- (3-morpholinoethoxy) -1H-benzimidazol-1-yl] -quinoline 139A (182 mg, 0.32 mmol), racemic BINAP (30 mg, 0.05 mmol), Cs ₂ CO ₃ (145 mg, 0.45 mmol), piperidine-4-yl-carbamic acid tert -butyl ester (127 mg, 0.64 mmol), xylenes (1 ml) and Pd (OAc) ₂ (7.1 mg, 0.032 mmol) were combined under argon and heated at reflux for two days. This reaction was carried out as in Example 138E, including chromatography, to give 120 mg of the title product 139B.

Example 139C

1 - [[2- [5- (3-morpholinoethoxy) -1H-benzimidazol-1-yl] -quinolin-8-yl]] - piperidin-4-ylamine trihydrochloride

{1- [[2- [5- (3-Morpholinoethoxy) -1H-benzimidazol-1-yl] -quinolin-8-yl]] - piperidin-4-yl} -carbamic acid tert -butyl ester 139B (121 mg, 0.21 mmol) was stirred at ambient temperature with 4N HCl in dioxane (0.63 mL, 2.5 mmol). After 4 h, the mixture was rotary evaporated and the residue stirred briefly with fresh anhydrous dioxane. Filtration gave the title product 139 as a pale yellow solid.
CI m / z 473 [M + 1]; ¹ H-NMR (DMSO) δ 9.67 (brs, 1H), 8.92 (d, J = 9.1Hz, 1H), 8.62 (d, J = 8.7Hz, 1H ), 8.50 (brs, 3H), 8.21 (d, J = 8.7 Hz, 1H), 7.76 (m, 1H), 7.69 (d, J = 8.3 Hz, 1 H), 7.55 (t, J = 7.9 Hz, 1 H), 7.44 (d, J = 2.5 Hz, 1 H), 7.40 (m, 1 H), 4.59 (m, 2H), 3.97 (d, J = 11.2Hz, 2H), 3.84 (m, 4H), 3.6-3.5 (m, 4H) , 3.21-3.24 (m, 3H), 2.86 (m, 2H), 2.09 (m, 4H).

Example 140 5- {2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} - [1,3,4] oxadiazol-2-ylamine

Example 140A

2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-carboxylic acid hydrazide

Methyl 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinoline-8-carboxylate 127 (1.00 g, 2.66 mmol) was dissolved in 10 mL of anhydrous THF under an atmosphere of dry N ₂ solved. To this solution was added 400 μl of anhydrous hydrazine and the solution was then stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo and the resulting residue was partitioned between DCM and aqueous saturated NaHCO ₃ . The DCM layer was washed again with aqueous saturated NaHCO ₃ , then brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The ge The residue formed was chromatographed on flash silica gel eluting with MeOH / DCM (5/95) to give 553 mg of the title compound 140A as a light yellow solid.

Example 140B

5- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} - [1,3,4] oxadiazol-2-ylamine

2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -quinoline-8-carboxylic acid hydrazide 140A (403mg, 1.07mmol) and NaHCO ₃ (275mg, 3.28mmol) were added in a Solution of 5 ml of 1,4-dioxane and 5 ml of water dissolved. To this solution was added 500 μl of a 3M solution of cyanogen bromide in DCM. The reaction mixture was heated to reflux temperature and reacted at this temperature for 48 hours. The reaction mixture was concentrated in vacuo and then partitioned between EtOAc and aqueous saturated NaHCO ₃ . The DCM layer was then washed with brine, dried over Na ₂ SO ₄ and filtered. A precipitate formed in the filtrate was collected by suction filtration and dried under vacuum to give 83.7 mg of the title compound 140 as a yellow solid.
CI m / z 403 [M + 1]; ¹ H NMR (DMSO) δ 9.18 (s, 1H), 8.75 (d, J = 8.7Hz, 1H), 8.68 (d, J = 9.1Hz, 1H ), 8.27 (d, J = 9.1 Hz, 1 H), 8.20 (dd, J = 1.2, 8.3 Hz, 1 H), 8.12 (m, 1 H), 7.70 (m, 1H), 7.30 (m, 1H), 7.28 (d, J = 2.5Hz, 3H), 6.97 (dd, J = 2.5, 8 , 7Hz, 1H), 4.14 (m, 2H), 3.67 (m, 2H), 3.31 (s, 3H).

Example 141 Ethyl 1- [8-4-aminopiperidin-1-yl] quinolin-2-yl] benzimidazole-5-carboxylate

Example 141A, B

Ethyl 1- [8 chloroquinoline-2-yl) -benzimidazole-5-carboxylate and ethyl 1- [8-chloroquinolin-2-yl) benzimidazole-6-carboxylate

2,8-dichloroquinoline (13.3 g, 67.2 mmol), sodium hydride (60% dispersion in mineral oil, 2.75 g, 68.8 mmol), 55 mL of toluene, and 109 mL of 1-methyl-2-pyrrolidinone were combined under nitrogen. Ethyl benzimidazole-5-carboxylate (12.81 g, 67.4 mmol) was added portionwise over 10 minutes and the reaction mixture was heated under reflux for 20 h. The cooled mixture was diluted with EtOAc (~450 mL) and water (~600 mL) was added slowly to allow crystallization of the product. Filtration gave 25g of light gray crystals, which were shown by ¹ H NMR analysis to contain both title regioisomers 141A, B in a ratio of about 3 to 2 in favor of the 5-carboxylate regioisomer 141A. Fractional crystallization from chloroform / ethanol allowed the separation of the regioisomers.
5'-esterregioisomer 141A: CI m / z 352 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.91 (d, J = 8.7 Hz, 1H), 8.75 (s, 1 H), 8.58 (s, 1 H), 8.40 ( d, J = 8.7Hz, 1H), 8.22 (d, J = 8.7Hz, 1H), 7.92 (d, J = 7.9Hz, 1H), 7.80 (d, J = 8.3Hz, 1H), 7.78 (d, J = 8.7Hz, 1H), 7.51 (m, 1H), 4.43 (q, J = - 7 Hz, 2 H), 1.44 (t, J = 7 Hz, 3 H).
6'-esterregioisomer 141B: CI m / z 352 [M + 1]; ¹ H-NMR _(CDCl3) δ 9.70 (s, 1 H), 8.82 (s, 1 H), 8.40 (d, J = 8.7 Hz, 1 H), 8.15 ( d, J = 8.7Hz, 1H), 7.93 (d, J = 7.5Hz, 1H), 7.89 (d, J = 8.3Hz, 1H), 7.80 (m, 2H), 7.51 (t, J = 7.9Hz, 1H), 4.44 (q, J = -7.2Hz, 2H), 1.46 (t, J = 7.1 Hz, 3 H).

Example 141C

Ethyl-1- [8- (4-tert-butoxycarbonylaminopiperidine-1-yl) -quinolin-2-yl] -benzimidazole-5-carboxylate

Ethyl 1- [8-chloro-quinolin-2-yl) -benzimidazole-5-carboxylate 141A (3.00 g, 8.53 mmol), racemic BINAP (806 mg, 1.29 mmol), Cs ₂ CO ₃ (4 , 00 g, 12.3 mmol), tert-butyl piperidin-4-ylcarbamate (3.49 g, 17.4 mmol), xylenes (26 ml) and Pd (OAc) ₂ (198 mg, 0, 88 mmol) were combined under argon and heated under reflux for three days. After cooling, hexanes (25 ml) were added and the mixture was stirred overnight. Solids were removed by filtration and washed repeatedly with hexanes (5 x 30 mL). The solids were then extracted with EtOAC (3 x 500 mL) and the EtOAC solutions were combined and concentrated evaporated, leaving 4.18 g of a greenish black foam. The title product 141C (2.06 g) was isolated as pale yellow crystals (mp 170-175 ° C) after silica gel chromatography (hexanes / EtOAc) followed by brief trituration with ethyl ether.

Example 141D

Ethyl-1- [8- (4-aminopiperidin-1-yl) -quinolin-2-yl] -benzimidazole-5-carboxylate

Ethyl 1- [8- (4-tert-butoxycarbonylaminopiperidin-1-yl) -quinolin-2-yl] -benzimidazole-5-carboxylate 141C (125 mg, 0.24 mmol) was treated at ambient temperature with 4N HCl in dioxane (0.62 ml, 2.5 mmol). After 4 h, the mixture was evaporated under reduced pressure. The solid residue was slurried in 0.5 ml of ethyl ether, filtered and dried under vacuum to give the title product 141 as the hydrochloride salt.
CI m / z 416 [M + 1]; ¹ H NMR (DMSO) δ 9.38 (s, 1H), 8.93 (d, J = 8.7Hz, 2H), 8.62 (d, J = 9.1Hz, 1H ), 8.37 (s, 1H), 8.30 (d, J = 8.7 Hz, 1H), 8.21 (d, J = 8.7 Hz, 1H), 8.16 ( brs, 3H), 7.68 (d, J = 8.3Hz, 1H), 7.54 (m, 1H), 7.37 (m, 1H), 4.36 (q, J = 7Hz, 2H), 3.88 (m, 2H), 3.22 (m, 1H), 2.84 (m, 2H), 2.08 (m, 2H), 1, 97-2.00 (m, 2H), 1.36 (t, J = 7Hz, 3H).

Example 142 1- [8- (4-Aminopiperidin-1-yl] quinolin-2-yl] benzimidazole-5-carboxylic acid

Example 142A

1- [8- (4-tert-butoxycarbonylaminopiperidine-1-yl) -quinolin-2-yl] -benzimidazole-5-carboxylic acid

Ethyl-1- [8- (4-tert-butoxycarbonylaminopiperidine-1-yl) -quinolin-2-yl] -benzimidazole-5-carboxylate 141C (1.300 g, 2.52 mmol), 1,4-dioxane (5.2 mL), MeOH (1.3 mL), and aqueous 1 N NaOH (3.9 mL, 3.9 mmol) was combined and heated at 70 ° C for 1 h. Allow to cool of the mixture became aqueous Add 1N HCl (3.9 mL, 3.9 mmol) slowly with stirring and then 120 ml EtOAC added. The precipitated solids were passed through Filtration to give 0.916 mg of the title product 142A were. An additional 264 mg of compound 142A were evaporated the filtrate-EtOAC layer recovered.

Example 142B

1- [8- (4-aminopiperidin-1-yl) -quinolin-2-yl] -benzimidazole-5-carboxylic acid

1- [8- (4-tert-Butoxycarbonylaminopiperidin-1-yl) -quinolin-2-yl] -benzimidazole-5-carboxylic acid 142A (51 mg, 0.105 mmol) was treated at ambient temperature with 4N HCl in 1,4-dioxane (0.26 ml, 1.04 mmol). After 4 h, the mixture was evaporated under reduced pressure. The solid residue was slurried briefly in 1 mL of Et ₂ O, filtered and dried under vacuum to afford the title product 142 as the hydrochloride salt.
CI m / z 388 [M + 1]; ¹ H NMR (DMSO) δ 9.36 (s, 1H), 8.95 (d, J = 8.3Hz, 1H), 8.60 (d, J = 9.1Hz, 1H ), 8.34 (s, 1H), 8.28 (d, J = 9.1Hz, 1H), 8.21 (d, J = 8.7Hz, 1H), 8.08 ( br, 3H), 7.66 (d, J = 8.3Hz, 1H), 7.52 (m, 1H), 7.34 (d, J = 7.1Hz, 1H), 3.85-3.88 (m, 2H), 3.20 (m, 1H), 2.81 (m, 2H), 2.06 (m, 2H), 1.95-1, 98 (m, 2H).

Example 143 N- (4-Morpholino) ethyl-1- [8- (4-aminopiperidin-1-yl) -quinolin-2-yl] -benzimidazole-5-carboxamide

Example 143A

N- (4-Morpholino) ethyl-1- [8- (4-tert-butoxycarbonylaminopiperidine-1-yl) -quinolin-2-yl] -benzimidazole-5-carboxamide

1- [8- (4-tert-Butoxycarbonylaminopiperidin-1-yl) -quinolin-2-yl] -benzimidazole-5-carboxylic acid 142A (146 mg, 0.30 mmol), DMF (1 mL) and 1.1 ' Carbonyldiimidazole were combined and stirred under nitrogen at ambient temperature for 2 h. 4- (2-Aminoethyl) morpholine (0.050 mL, 0.38 mmol) was added and the mixture was stirred at ambient temperature for 16 h. EtOAc (10 mL) and saturated aqueous NaHCO ₃ (5 mL) were added and stirred for 30 min. The white precipitate was collected by filtration and dried under vacuum to give 158 mg of the title compound 143A.

Example 143B

N- (4-Morpholino) ethyl-1- [8- (4-aminopiperidin-1-yl) -quinolin-2-yl] -benzimidazole-5-carboxamide

N- (4-Morpholino) ethyl 1- [8- (4-tert-butoxycarbonylamino-piperidin-1-yl) -quinolin-2-yl] -benzimidazole-5-carboxamide (133 mg, 0.22 mmol) stirred at ambient temperature with 4N HCl in dioxane (2.0 mL, 8 mmol). After 4 h, the mixture was evaporated under reduced pressure, added twice with 2 mL of 1,4-dioxane and evaporated to leave a solid residue which was slurried in 3 mL of Et ₂ O, filtered and dried under vacuum to give the title product 143 was obtained as its bis-HCl salt.
CI m / z 500 [M + 1]; ¹ H-NMR (DMSO) δ 9.43 (s, 1H), 9.07-9.12 (m, 2H), 8.61 (m, 2H), 8.46 (br, 3H ), 8.38 (s, 1H), 8.23 (d, J = 8.7 Hz, 1H), 7.68 (m, 1H), 7.54 (m, 1H), 7 , 39 (m, 1H), 3.95-3.98 (m, 2H), 3.78-3.84 (m, 4H), 3.70-3.74 (m, 2H) , 3.57-3.68 (m, 2H), 3.36-3.38 (m, 2H), 3.11-3.23 (m, 3H), 2.85 (m, 2 H), 2.11 (m, 4H).

Example 144 4- {1- [8- (4-Aminopiperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yl} -benzaldehyde

The procedure used for Example 118 was followed, but using 4-formylbenzene boronic acid in place of phenylboronic acid in Example 118B to give the title compound 144 as the bis-HCl salt.
CI m / z 448 [M + 1]; ¹ H-NMR (DMSO) δ 10.08 (s, 1H), 9.56 (s, 1H), 9.08 (d, J = 8.7Hz, 1H), 8.64 (i.e. , J = 8.7 Hz, 1H), 8.40 (brs, 4H), 8.33 (d, J = 8.7 Hz, 1H), 8.25 (s, 1H), 8 , 13 (d, J = 8.3 Hz, 2 H), 8.02 (d, J = 8.3 Hz, 1 H), 7.73 (d, J = 7.5 Hz, 1 H), 7.58 (m, 2H), 7.44 (m, 1H), 3.91 (m, 2H), 3.26 (m, 1H), 2.92 (m, 2H), 2.14 (m, 4H).

Example 145 1- {2- [5- (4-Methylaminomethyl-phenyl) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine

4- {1- [8- (4-Aminopiperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yl} -benzaldehyde 144 (205 mg, 0.374 mmol) was dissolved in a 3 mL solution MeOH and 2 ml of DCE were dissolved under an atmosphere of dry N ₂ . To this solution was added 935 μl of a solution of 2.0 M methylamine in MeOH, and then AcOH was added dropwise to ~5 pH of the solution. To this solution was added NaCNBH ₃ (47 mg, 0.75 mmol) and the reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was then concentrated in vacuo and then partitioned between a solution of 2-propanol / DCM (18/82) and 0.1 N aqueous NaOH. The water layer was washed two more times with a solution of 2-propanol / DCM (18/82). The organic extracts were combined and concentrated in vacuo to give a yellow foam. The foam was chromatographed on flash silica gel eluting with a gradient of DCM / MeOH / NH ₄ OH (2 / 97.8 / 0.2) to DCM / MeOH / NH ₄ OH (10 / 99.8 / 0.2). whereby 83 mg of a yellow foam were obtained. The foam was dissolved in 2 ml of EtOH in a pressure vial. To this solution was added 50 μl of concentrated HCl. The reaction mixture was heated to ~ 90 ° C and reacted at this temperature for 2 h. The reaction mixture was then cooled to ambient temperature and the precipitate formed was recovered by suction filtration. The solid was dried under vacuum to give 82 mg of the tri-HCl salt of the title compound 145 as a white solid.
CI m / z 463 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 10.57 (s, 1 H), 8.90 (d, J = 8.7 Hz, 1 H), 8.75 (d, J = 9.5 Hz, 1 H), 8.32 (d, J = 9.1 Hz, 1 H), 8.23 (m, 2 H), 8.16 (d, J = 8.3 Hz, 1 H), 8, 03 (d, J = 8.3Hz, 1H), 7.94 (d, J = 8.3Hz, 2H), 7.86 (m, 1H), 7.67 (d, J = 8.3Hz, 2H), 4.28 (s, 2H), 4.18 (m, 2H), 3.73 (m, 2H), 3.63 (m, 1H), 2 , 77 (s, 3H), 2.48 (m, 2H), 2.41 (m, 2H).

Example 146 1- {2- [5- (4-Dimethylaminomethyl-phenyl) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine

The procedure used for Example 145 was followed, but using a solution of 2.0 M dimethylamine in MeOH instead of the solution of 2.0 M methylamine in MeOH to give the tri-HCl salt of the title compound 146 as a white solid ,
CI m / z 477 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 10.74 (s, 1 H), 8.97 (d, J = 9.1 Hz, 1 H), 8.70 (d, J = 8.7 Hz, 1 H), 8.39 (d, J = 9.1 Hz, 1 H), 8.28 (m, 4 H), 7.97 (d, J = 8.3 Hz, 2 H), 7, 93 (m, 1H), 7.72 (d, J = 8.3Hz, 2H), 4.43 (s, 2H), 4.22 (m, 2H), 3.97 (m , 2H), 3.73 (m, 1H), 2.91 (s, 6H), 2.61 (m, 2H), 2.49 (m, 2H).

Example 147 1- (2- {2- [5- (2-Methylimidazol-1-yl) -ethoxy] -benzimidazol-1-yl} -quinolin-8-yl) -piperidin-4-ylamine

Example 147A

Methanesulfonic acid 2- {1- [8- (4-tert-butoxycarbonylamino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yloxy} -ethyl ester

2- {1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yloxy} -ethanol 83 (1.89 g, 4.68 mmol) and Di-tert-butyl dicarbonate (1.02 g, 4.68 mmol) was added to a solution of 40 mL of anhydrous DCM and 20 mL of anhydrous THF under an atmosphere of dry N ₂ . The heterogeneous reaction mixture was stirred at ambient temperature for 3 hours after which 1.2 ml of NEt ₃ and then 2.10 ml of methanesulfonyl chloride were added. The reaction mixture was stirred at ambient temperature for 48 h and then partitioned between DCM and aqueous saturated NaHCO ₃ . The DCM layer was obtained and washed two more times with aqueous saturated NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a yellow foam as the title compound 147A and used without further purification.

Example 147B

1- (2- {5- [2- (2-methylimidazol-1-yl) -ethoxy] -benzoimidazol-1-yl) -quinolin-8-yl) -piperidin-4-ylamine

Methanesulfonic acid 2- {1- [8- (4-tert-butoxycarbonylamino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yloxy} -ethyl ester 147A (344 mg, 0.591 mmol) slurried in 2.0 ml of anhydrous DMF under an atmosphere of dry N ₂ . To this heterogeneous solution was added 2-methylimidazole (53 mg, 0.65 mmol) followed by sodium hydride (60% in oil) (16 mg, 0.65 mmol). The reaction mixture was then heated to 60 ° C. After 1 h, the reaction mixture was cooled to ambient temperature and treated with 26 mg of further sodium hydride (60% in oil). The reaction mixture was reheated to 60 ° C and reacted at this temperature overnight. The reaction mixture was cooled to ambient temperature and then quenched with water. The reaction mixture was concentrated in vacuo and the resulting brown oil was partitioned between DCM and aqueous 1.0 NaOH. The DCM layer was obtained and washed two more times with aqueous 1.0 M NaOH, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was chromatographed on flash silica gel eluting with a gradient of DCM / MeOH / NH ₄ OH (2 / 97.8 / 0.2) to DCM / MeOH / NH ₄ OH (10 / 89.8 / 0.2) to give 158 mg of a yellow foam. The foam was dissolved in 1 ml of TFA under an atmosphere of dry N ₂ and stirred at ambient temperature for 1 h. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between DCM and aqueous 0.1 M NaOH. The water layer was washed twice more with DCM. The DCM extracts were combined, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 128 mg of the title compound 147.
CI m / z 468 [M + 1]; ¹ H-NMR _(CDCl3) δ 8.63 (s, 1 H), 8.37 (d, J = 9.1 Hz, 1 H), 8.28 (d, J = 8.7 Hz, 1 H), 7.64 (d, J = 8.7Hz, 1H), 7.46 (m, 2H), 7.26 (d, J = 2.5Hz, 1H), 7.22 (m, 1H), 6.97 (m, 2H), 6.91 (d, J = 1.3Hz, 1H), 4.28 (s, 4H), 3.88 (m, 2H), 2.88 (m, 3H), 2.46 (s, 3H), 2.05 (m, 2H), 1.86 (brs, 2H), 1.80 (m, 2H).

Example 148 1- {2- [5- (2- [1,2,4] -triazol-1-yl-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine

Methanesulfonic acid 2- {1- [8- (4-tert-butoxycarbonylamino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yloxy} -ethyl ester 147A (500mg, 0.860mmol) slurried in 2.0 ml of anhydrous DMF under an atmosphere of dry N ₂ . To this heterogeneous solution was added 1,2,4-triazole (65 mg, 0.95 mmol) followed by sodium hydride (60% in oil) (23 mg, 0.95 mmol). The reaction mixture was then heated to 60 ° C and reacted at this temperature for 3 hours. The reaction mixture was cooled to ambient temperature, then quenched with water. The reaction mixture was concentrated in vacuo and the resulting brown oil was partitioned between a solution of 2-propanol / DCM (18/82) and aqueous 0.1 M NaOH. The organic layer was obtained and washed two more times with aqueous 0.1 M NaOH, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to a yellow oil. The yellow oil was chromatographed on flash silica gel eluting with DCM / MeOH / NH ₄ OH (1.5 / 98.4 / 0.1) to give 126 mg of a yellow foam. The foam was dissolved in 2 ml of EtOH in a pressure vial. To this solution was added 75 μl of concentrated HCl. The reaction mixture was heated to ~ 90 ° C and reacted at this temperature for 2 h. The reaction mixture was then cooled to ambient temperature and the precipitate formed was recovered by suction filtration. The solid was dried under vacuum to give 86 mg of the bis-HCl salt of the title compound 148 as a yellow solid.
CI m / z 455 [M + 1]; ¹ H-NMR (CD ₃ OD) δ 10.46 (s, 1 H), 9.71 (s, 1 H), 8.84 (d, J = 9.7 Hz, 1 H), 8.73 (s, 1H), 8.60 (d, J = 9.1Hz, 1H), 8.23 (d, J = 8.7Hz, 1H), 8.10 (d, J = 8 , 3 Hz, 1 H), 8.00 (d, J = 7.5 Hz, 1 H), 7.83 (m, 1 H), 7.54 (dd, J = 2.5, 9.1 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 4.93 (m, 2H), 4.67 (m, 2H), 4.12 (m, 2 H), 3.60 (m, 3H), 2.37 (m, 4H).

Claims (20)

Compound of the formula

or a pharmaceutically acceptable salt, prodrug or pharmaceutically acceptable solvate thereof, wherein: X is CH or N; R ^{1 is} - (CR ⁴ R ⁵ ) _t C (O) OR ³ , - (CR ⁴ R ⁵ ) _t C (O) NR ³ R ⁴ , - (CR ⁴ R ⁵ ) _t OR ³ , - (CR ⁴ R ⁵ ) _t C (O) (C ₃ -C ₁₀ -cycloalkyl), - (CR ⁴ R ⁵ ) _t C (O) (C ₆ -C ₁₀ -aryl), - (CR ⁴ R ⁵ ) _t C ( O) (4- to 10-membered heterocyclyl), - (CR ⁴ R ⁵ ) _t (C ₃ -C ₁₀ -cycloalkyl), - (CR ⁴ R ⁵ ) _t (C ₆ -C ₁₀ -aryl) and - ( CR ⁴ R ⁵ ) _t (4- to 10-membered heterocyclyl) wherein each t is independently an integer from 0 to 5; wherein the cycloalkyl, aryl and heterocyclyl moieties of R ^{1 are} optionally fused to a benzene ring, a C ₅ -C ₈ cycloalkyl group or a 4- to 10-membered heterocyclic group; the - (CR ⁴ R ⁵ ) _t units of the aforementioned R ¹ groups optionally comprise a carbon-carbon double or triple bond when t is an integer between 2 and 5; the abovementioned R ¹ groups are optionally substituted by 1 or 2 groups independently of one another selected from -NR ³ R ⁴ , -OR ³ , C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl and C ₂ - C ₁₀ alkynyl are selected, wherein the alkyl, alkenyl and alkynyl groups are substituted by 1 or 2 groups independently selected from -NR ³ R ⁴ and -OR ³ ; and the aforementioned R ¹ groups are optionally substituted with 1 to 3 R ² groups; each R ^{2 is} independently selected from H, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₁₀ cycloalkyl, oxo, halogen, cyano, nitro, trifluoromethyl, Difluoromethoxy, trifluoromethoxy, azido, -OR ³ , -C (O) R ³ , -C (O) OR ³ , -NR ⁴ C (O) OR ⁶ , -OC (O) R ³ , -NR ⁴ SO ₂ R ⁶ , -SO ₂ NR ³ R ⁴ , -NR ⁴ C (O) R ³ , -C (O) NR ³ R ⁴ , -NR ⁵ C (O) NR ³ R ⁴ , -NR ³ R ⁴ , -S (O) _j (CR ⁴ R ⁵ ) _m (C ₆ -C ₁₀ aryl), -S (O) _j (C ₁ -C ₆ alkyl), wherein j is an integer from 0 to 2, - ( CR ⁴ R ⁵ ) _m (C ₆ -C ₁₀ aryl), -O (CR ⁴ R ⁵ ) _m (C ₆ -C ₁₀ aryl), -NR ⁴ (CR ⁴ R ⁵ ) _m (C ₆ -C ₁₀ -aryl), -O (CR ⁴ R ⁵ ) _m (4- to 10-membered heterocycle), -NR ⁴ (CR ⁴ R ⁵ ) _m (4- to 10-membered heterocycle), - (CR ⁴ R ⁵ ) _m (4- to 10-membered heterocyclyl) and - (CR ⁴ R ⁵ ) _m (C ₃ -C ₁₀ -cycloalkyl) wherein each m is independently an integer from 0 to 4; wherein the alkyl, alkenyl and alkynyl groups optionally contain 1 or 2 hetero units selected from O, -S (O) _j -, wherein j is an integer from 0 to 2, and -N (R ³ ) -, with the proviso that two O atoms, two S atoms, or one O and one S atom are not directly attached to each other, and the proviso that an O atom, an S atom, or an N atom is not directly is bonded to a triple bond or a non-aromatic double bond; wherein the cycloalkyl, aryl and heterocyclic groups of R ^{2 are} optionally fused to a C ₆ -C ₁₀ aryl group, C ₅ -C ₈ cycloalkyl group or a 4- to 10-membered heterocyclic group; and the alkyl, cycloalkyl, aryl and heterocyclic groups of R ^{2 are} optionally substituted with 1 to 5 substituents independently of one another selected from oxo (= O), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, NR ⁴ SO ₂ R ⁶ , -SO ₂ NR ³ R ⁴ , C (O) R ³ , -C (O) OR ³ , -OC (O) R ³ , -NR ⁴ C (O) OR ⁶ , -NR ⁴ C (O) R ³ , -C (O) NR ³ R ⁴ , -NR ³ R ⁴ , -OR ³ , C ₁ -C ₁₀ alkyl, - (CR ⁴ R ⁵ ) _m (C ₆ -C ₁₀ -Aryl) and - (CR ⁴ R ⁵ ) _m (4- to 10-membered heterocyclyl) wherein each m is independently an integer ranging from 0 to 4; each R ^{3 is} independently H, C ₁ -C ₁₀ alkyl, - (CR ⁴ R ⁵ ) _m (C ₆ -C ₁₀ aryl) and - (CR ⁴ R ⁵ ) _m (4- to 10-membered heterocyclyl ), wherein each m is independently an integer of 0 to 4, is selected; wherein the alkyl group optionally comprises 1 or 2 hetero units selected from O-, -S (O) _j -, wherein j is an integer in the range of 0 to 2, and -N (R ⁴ ) -, with the proviso in that two O atoms, 2 S atoms or one O and one S atom are not directly bonded to each other; the cycloalkyl, aryl and heterocyclic groups of R ^{3 are} optionally fused to a C ₆ -C ₁₀ aryl group, C ₅ -C ₈ cycloalkyl group or a 4- to 10-membered heterocyclic group; and the abovementioned R ³ substituents, with the exception of H, are optionally substituted by 1 to 5 substituents independently of one another from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -C (O) R ⁴ , -C (O) OR ⁴ , -OC (O) R ⁴ , -NR ⁴ C (O) R ⁵ , -C (O) NR ⁴ R ⁵ , -NR ⁴ R ⁵ , hydroxy, C ₁ -C ₆ - Alkyl and C ₁ -C ₆ alkoxy are selected; each R ⁴ and R ^{5 is} independently H or C ₁ -C ₆ alkyl; or when R ⁴ and R ^{5 are} attached to the same carbon or nitrogen atom, R ⁴ and R ^{5 taken} together with the carbon or nitrogen can form a 4- to 10-membered ring which may be carbocyclic or heterocyclic; each R ^{6 is selected} from the substituents specified in the definition of R ³ , except that R ^{6 is} not H; each R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ^{11 is} independently selected from the group of substituents given in the definition of R ² . A compound according to claim 1, wherein R ^{1 is} C ₆ -C ₁₀ aryl or 4- to 10-membered heterocyclyl, wherein the aforementioned R ¹ groups are each substituted with 1 or 2 groups independently selected from -NR ³ R ⁴ , -OR ³ and C ₁ -C ₃ alkyl are selected, wherein the alkyl groups are substituted with 1 or 2 groups independently selected from -NR ³ R ⁴ and -OR ³ ; and the aforementioned R ¹ groups are optionally substituted with 1 to 3 R ² groups; each R ² independently of H, C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, oxo (= O), -OR ³ , -C (O) R ³ , -C (O) OR ³ , -NR ⁴ C (O) R ³ , -C (O) NR ³ R ⁴ , -NR ³ R ⁴ , -NR ⁴ SO ₂ R ⁶ , -SO ₂ NR ³ R ⁴ , - (CR ⁴ R ⁵ ) _m (4- to 10-membered heterocyclyl) and (R ⁴ R ⁵ ) _m (C ₃ -C ₁₀ -cycloalkyl); and the alkyl groups optionally contain 1 or 2 hetero units selected from O, -S (O) _j -, wherein j is an integer of 0 to 2, and -N (R ³ ) -, with the proviso that two O atoms, two S atoms, or one O and one S atom are not directly bonded to each other; and the alkyl and cycloalkyl groups of R ^{2 are} optionally substituted with 1 to 5 substituents independently selected from oxo, cyano, trifluoromethyl, trifluoromethoxy, -NR ⁴ SO ₂ R ⁶ , -SO ₂ NR ³ R ⁴ , -C (O ) R ³ , -C (O) OR ³ , -NR ⁴ C (O) OR ⁶ , -NR ⁴ C (O) R ³ , -C (O) NR ³ R ⁴ , -NR ³ R ⁴ , -OR ³ and C ₁ -C ₁₀ alkyl, wherein each m is independently an integer in the range of 0 to 4. A compound according to claim 1, wherein R ^{1 is} piperidinyl, piperazinyl or phenyl, wherein the R ¹ groups are substituted with -NR ³ R ⁴ , oxo (= O), -OR ³ and C ₁ -C ₃ alkyl, wherein the Alkyl group is optionally substituted with 1 or 2 groups independently selected from -NR ³ R ⁴ and -OR ³ ; and the aforementioned R ¹ groups are optionally substituted with 1 to 3 R ² groups. A compound according to claim 2, wherein the R ¹ groups are substituted with -NR ³ R ⁴ , oxo (= O), OR ³ or C ₁ -C ₃ alkyl wherein the alkyl group is optionally substituted with -NR ³ R ⁴ . A compound according to claim 1, wherein R ¹ is phenyl substituted with pyrrolidin-1-yl, said pyrrolidin-1-yl being optionally substituted with 1 to 3 substituents independently selected from oxo, cyano, trifluoromethyl, trifluoromethoxy, -NR ⁴ SO ₂ R ⁶ , -SO ₂ NR ³ R ⁴ , -C (O) R ³ , -C (O) OR ³ , -NR ⁴ C (O) OR ⁶ , -NR ⁴ C (O) R ³ , -C (O) NR ³ R ⁴ , -NR ³ R ⁴ , -OR ³ and C ₁ -C ₁₀ alkyl are selected; and R ^{11 is} -OR ³ . A compound according to claim 5 wherein R ^{1 is} 4-pyrrolidin-1-ylmethylphenyl optionally substituted with 1 to 3 substituents independently selected from oxo, cyano, trifluoromethyl, trifluoromethoxy, -NR ⁴ SO ₂ R ⁶ , -SO ₂ NR ³ R ⁴ , -C (O) R ³ , -C (O) OR ³ , -NR ⁴ C (O) OR ⁶ , -NR ⁴ C (O) R ³ , -C (O) NR ³ R ⁴ , -NR ³ R ⁴ , -OR ³ and C ₁ -C ₁₀ alkyl are selected; and R ^{11 is} -OR ³ . A compound according to claim 6 wherein R ^{11 is} joined to the 5-position of the benzimidazole moiety of the compound of formula 1 and is -OR ³ . A compound according to claim 7 wherein R ^{11 is} joined to the 5-position of the benzimidazole moiety of the compound of formula 1 and is 2-methoxyethoxy. A compound according to claim 1, wherein R ^{1 is} pyrrolidin-1-yl or piperidin-1-yl, wherein the R ^{1 is} optionally substituted with 1 to 3 substituents independently selected from oxo, cyano, trifluoromethyl, trifluoromethoxy, -NR ⁴ SO ₂ R ⁶ , -SO ₂ NR ³ R ⁴ , -C (O) R ³ , -C (O) OR ³ , -NR ⁴ C (O) OR ⁶ , -NR ⁴ C (O) R ³ , -C (O) NR ³ R ⁴ , -NR ³ R ⁴ , -OR ³ and C ₁ -C ₁₀ alkyl are selected. A compound according to claim 9, wherein R ^{1 is} pyrrolidin-1-yl or piperidin-1-yl substituted with -NR ³ R ⁴ and optionally substituted with 1 or 2 substituents independently selected from oxo, cyano, trifluoromethyl, trifluoromethoxy , -NR ⁴ SO ₂ R ⁶ , -SO ₂ NR ³ R ⁴ , -C (O) R ³ , -C (O) OR ³ , -NR ⁴ C (O) OR ⁶ , -NR ⁴ C (O) R ³ , -C (O) NR ³ R ⁴ , -NR ³ R ⁴ , -OR ³ and C ₁ -C ₁₀ alkyl are selected; and R ^{11 is} -OR ³ . A compound according to claim 10 or claim 9, wherein R ^{11 is} joined to the 5-position of the benzimidazole moiety of the compound of formula 1 and is -OR ³ and R ⁹ and R ^{10 are} both H. A compound according to claim 10 or claim 9 wherein R ^{11 is} joined to the 5-position of the benzimidazole moiety of the compound of formula 1 and is 2-methoxyethoxy and R ⁹ and R ^{10 are} both H. A compound according to claim 1, wherein R ^{9 is} -C (O) R ³ , wherein R ^{3 is} pyrrolidin-1-yl or azetidin-1-yl, wherein the R ³ groups are optionally substituted with 1 to 3 substituents independently from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -C (O) R ⁴ , -C (O) OR ⁴ , -OC (O) R ⁴ , -NR ⁴ C (O) R ⁵ , -C (O) NR ⁴ R ⁵ , -NR ⁴ R ⁵ , hydroxy, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy. A compound according to claim 1 which is selected from the group consisting of: [1- [2- (5-methoxy-benzimidazol-1-yl) quinolin-8-yl] -piperidin-4-ylamine; 1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-ol; 1- {2- [5- (pyridin-2-ylmethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; {1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -dimethyl-amine; {4- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -methyl-amine; {4- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -dimethyl-amine; Cyclopropyl- {4- [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -amine; tert-butyl {4- [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -amine; 4- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] benzylamine; 1- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine; {1- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -dimethyl-amine; 1- [2- (5-trifluoromethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine; {4- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -methyl-amine; Cyclopropyl- {4- [2- (5-ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -amine; tert-butyl {4- [2- (5-ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -amine; {4- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -dimethyl-amine; 1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-one; 1- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-one; 1- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ol; tert-butyl {1- [2- (5-ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -amine; {1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -methyl-amine; 2- (5-Methoxy-benzimidazol-1-yl) -8- (1-oxa-6-aza-spiro [2.5] oct-6-yl) -quinoline; 4-dimethylaminomethyl-1- [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ol; 1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -4-methylaminomethyl-piperidin-4-ol; 4-Aminomethyl-1- [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ol; 1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -pyrrolidin-3-ylamine; 1- (2-benzimidazol-1-yl-quinolin-8-yl) -piperidin-4-ylamine; 1- (2-imidazo [4,5-b] pyridin-3-yl-quinolin-8-yl) -piperidin-4-ylamine; 1- {2- [5- (4-methoxy-phenyl) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; 1- [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine; 1- {2- [5- (3-Dimethylamino-propoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; 1- {2- [5- (3-Amino-propoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; 1- {2- [5- (2-Dimethylamino-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; 1- {2- [5- (pyridin-4-ylmethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; 1- [2- (5-Benzyloxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine; 1- {2- [5- (pyridin-3-ylmethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; 1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; 1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidine-4-carboxylic acid ethyl ester; 1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidine-4-carboxylic acid; 4-dimethylaminomethyl-1- [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ol; N- {1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -acetamide; N- {1- [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -acetamide; 1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ol; {1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -urea; 4-Aminomethyl-1- {2- [5- (pyridin-2-ylmethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ol; Cyclopropyl- (1- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) amine; (1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -dimethyl-amine; (1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -methyl-amine; (1- {2- [5- (3-Dimethylamino-propoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -dimethyl-amine; {1- [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -methyl-amine; {1- [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -dimethyl-amine; 2-Amino-N- (1- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -acetamide; - (S) -2-Amino-N- (1- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -propionamide; - (R) -2-Amino-N- (1- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -propionamide ; 2-Amino-N- (1- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -isobutyramide; 1- (1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamino) -2-methyl-propan-2-ol; (1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -pyridin-2-yl-methylamine; (1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -pyridin-3-ylmethyl-amine; 4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -phenol; [2- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -phenoxy) -ethyl] -dimethyl-amine; 2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8-piperazin-1-yl-quinoline; [2- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -ethyl] -dimethyl-amine; 2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8- (4-pyridin-2-ylmethyl-piperazin-1-yl) -quinoline; 2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8- (4-pyridin-3-ylmethyl-piperazin-1-yl) -quinoline; 2-Amino-1- (4- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -2-methyl-propane 1-one; (S) -2-amino-1- (4- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -propan 1-one; (S) -2-amino-1- (4- {2- [5- (2-methoxy-ethoxy) benzimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -propan-1 -one; 2-amino-1- (4- {2- [5- (2-methoxy-ethoxy) -benzenedimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl} -ethanone; (1-amino -cyclopropyl) - (4- {2- [5- (2-methoxyethoxy) benzimidazol-1-yl] quinolin-8-yl} -piperazin-1-yl) -methanone; 2- (4- { 2- (5- (2-methoxyethoxy) benzimidazol-1-yl] quinolin-8-yl} -piperazin-1-yl) -ethylamine; (R) -2-amino-3- (4- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -propan-1-ol; 3- {2- [5- (2-methoxy -ethoxy) benzimidazol-1-yl] -quinolin-8-yl} -3-azabicyclo [3.1.0] hex-6-ylamine; (S) -1- {2- [5- (2-methoxy- ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -pyrrolidin-3-ylamine; (R) -1- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] - quinolin-8-yl} -pyrrolidin-3-ylamine; 2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -8-pyridin-3-yl-quinoline; 2- [5- (2 -Methoxy-ethoxy) -benzimidazol-1-yl] -8- (6-methoxypyridin-3-yl) -quinoline; 4- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl ] -quinolin-8-yl} -benzoic acid methyl ester; 1- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -4-methyl-piperidin-4-ylamine 1- [2- (6, 7-Dihydro-5,8-dioxa-1,3-diaza-cyclopenta [b] naphthalen-1-yl) -quinolin-8-yl] -piperidin-4-ylamine; 2- {1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yloxy} -ethanol; 4-cyclopropylaminomethyl-1- {2- [5- (2-methoxy-ethoxy) benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ol; 1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazole-5-sulfonic acid dimethylamide; 1- [2- (6-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine; 1- [2- (5,6-Dimethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine; 2-dimethylamino-1- (4- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) ethanone; 1- [2- (5-Benzyloxy-benzimidazol-1-yl) -quinolin-8-yl] -4-methyl-piperidin-4-ol; (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -dimethyl-amine; (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -methyl-amine; 2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8- (4-morpholin-4-ylmethyl-phenyl) -quinoline; 2- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzylamino) -ethanol; 4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzylamine; 2- [5- (2-Methoxy-ethoxy) -benzimidazol-1-yl] -8- (4-pyrrolidin-1-ylmethyl-phenyl) -quinoline; 2- [5- (2-Methoxy-ethoxy) -benzimidazole 1-yl] -8- (4-pyrrolidin-1-ylmethyl-phenyl) -quinoline; 2- [5- (2-methoxyethoxy) -benzimidazol-1-yl] -8- (4-pyrrolidin-1 -ylmethyl-phenyl) -quinoline; 1- (4- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -benzyl) -cis -pyrrolidine-3, 4-diol; R, R- (1- (4- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -benzyl) -trans -pyrrolidine-3 , 4-diol); 1- (4- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -benzyl) -pyrrolidin-3-ol; R- (1- (4- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -benzyl) -pyrrolidin-3-ol); S- (1- (1) 4- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -benzyl) -pyrrolidin-3-ol); 1- (4- {2- [5 - (2-methoxyethoxy) benzimidazol-1-yl] quinolin-8-yl} benzyl) azetidin-3-ol; 2- [5- (2-methoxyethoxy) benzimidazol-1-yl ] -8- [4- (4-methylpiperazin-1-ylmethyl) -phenyl] -quinoline; 4- (4- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] - quinoline-8-yl} -benzyl) -pi perazine-1-carboxylic acid tert-butyl ester; [1- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -piperidin-4-yl] -carbamic acid tert-butyl ester; 1- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -piperidin-4-ylamine; (1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -methanol; (1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylmethyl) -methyl-amine; 2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8- [4- (4-methyl-piperazin-1-ylmethyl) piperidin-1-yl] quinoline; (1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylmethyl) -dimethyl-amine; 1- (1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylmethyl) -pyrrolidin-3-ol; C- (1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -methyl-amine; 1- {2- [5- (2-Dimethylamino-ethoxy) benzimidazol-1-yl] -quinolin-8-yl} -4-methyl-piperidin-4-ol; 1- {2- [5- (2-Dimethylamino-ethoxy) benzimidazol] -quinolin-8-yl} -piperidin-4-ol; S, S- (1- (4- {2- [5- (2-Methoxy-ethoxy) benzimidazol-1-yl] -quinolin-8-yl} -benzyl) -trans-pyrrolidine-3,4-diol) ; 4- {2- [5- (3-Amino-propoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -phenol; 4- {2- [5- (3-Dimethylamino-propoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -phenol; 1- [2- (5-Phenyl-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine; 1- [2- (5-pyridin-4-yl-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine; 1- {2- [5- (3-Methoxy-phenyl) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; 1- {2- (5-pyridin-3-yl-benzimidazol-1-yl) -quinolin-8-yl} -piperidin-4-ylamine; 1- {2- [5- (6-methoxy-pyridin-3-yl) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; 1- {2- [5- (4-Aminomethyl-phenyl) benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; 4- {1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yl} -benzoic acid methylester; 4- {1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yl} -phenol; 2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-carbonsäuremethylester; 2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-carbonsäuremethylester; 2- (5-Methoxy-benzimidazol-1-yl) -quinoline-8-carboxylic acid (2-dimethylamino-ethyl) -amide; 2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-carbonsäuremethylester; [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -pyrrolidin-1-yl-methanone; [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -morpholin-4-yl-methanone; [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-1-yl-methanone; (3-Amino-pyrrolidin-1-yl) - [2- (5-cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -methanone; 8-Allyloxy-2- (5-methoxy-benzimidazol-1-yl) -quinoline; {2- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yloxy] -ethyl} -methyl-amine; {2- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yloxy] -ethyl} -dimethyl-amine; 2- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yloxy] -ethylamine; 1 - [[2- [5- (3-morpholinoethoxy) -1H-benzimidazol-1-yl] -quinolin-8-yl]] - piperidin-4-ylamine trihydrochloride; 1 - [[2- [5- (3-morpholinoethoxy) -1H-benzimidazol-1-yl] -quinolin-8-yl]] - piperidin-4-ylamine trihydrochloride; 5- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} - [1,3,4] oxadiazol-2-ylamine; Ethyl-1- [8- (4-aminopiperidin-1-yl) -quinolin-2-yl] -benzimidazole-5-carboxylate; 1- [8- (4-aminopiperidin-1-yl) -quinolin-2-yl] -benzimidazole-5-carboxylic acid; N- (4-Morpholino) ethyl-1- [8- (4-aminopiperidin-1-yl) -quinolin-2-yl] -benzimidazole-5-carboxamide; 4- {1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yl} -benzaldehyde; 1- {2- [5- (4-Methylaminomethyl-phenyl) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; 1- {2- [5- (4-dimethylaminomethyl-phenyl) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; 1- (2- {2- [2- (2-Methyl-imidazol-1-yl) -ethoxy] -benzimidazol-1-yl} -quinolin-8-yl) -piperidin-4-ylamine and 1- {2 - [5- (2- [1,2,4] triazol-1-yl-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine, and the pharmaceutically acceptable salts, prodrugs and solvates of the compounds mentioned above. A compound according to claim 1 which is selected from the group of: 1- [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine; 1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-ol; 1- {2- [5- (pyridin-2-ylmethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; {1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -dimethyl-amine; {4- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -methyl-amine; {4- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -dimethyl-amine; 1- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine; {1- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -dimethyl-amine; {4- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -methyl-amine; {4- [2- (5-Ethoxy-benzimidazol-1-yl) -quinolin-8-yl] -benzyl} -dimethyl-amine; {1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -methyl-amine; 4-dimethylaminomethyl-1- [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ol; 1- [2- (5-Methoxy-benzimidazol-1-yl) -quinolin-8-yl] -4-methylaminomethyl-piperidin-4-ol; 4-Aminomethyl-1- [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ol; 1- {2- [5- (4-methoxy-phenyl) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; 1- [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine; 1- {2- [5- (3-Dimethylamino-propoxy) benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; 1- {2- [5- (3-Amino-propoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; 1- {2- [5- (2-Dimethylamino-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; 1- {2- [5- (pyridin-4-ylmethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; 1- [2- (5-Benzyloxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine; 1- {2- [5- (pyridin-3-ylmethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; 1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; 4-dimethylaminomethyl-1- [2- (5-methoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ol; 4-Aminomethyl-1- {2- [5- (pyridin-2-ylmethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ol; 1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -dimethyl-amine; 1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -methyl-amine; (1- {2- [5- (3-Dimethylamino-propoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -dimethyl-amine; {1- [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -methyl-amine; {1- [2- (5-Cyclopropylmethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-yl} -dimethyl-amine; (1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -pyridin-2-ylmethyl-amine; (1- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-yl) -pyridin-3-ylmethyl-amine; 4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -phenol; [2- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -phenoxy) -ethyl] -dimethyl-amine; 2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8-piperazin-1-yl-quinoline; [2- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -ethyl] -dimethyl-amine; 2-Amino-1- (4- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -2-methyl-propane 1-one; (S) -2-amino-1- (4- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -propan 1-one; (S) -2-amino-1- (4- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) -propan 1-one; 2-Amino-1- (4- {2- [5- (2-methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) ethanone; 2- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -piperazin-1-yl) ethylamine; 3- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -3-aza-bicyclo [3.1.0] hex-6-ylamine; 1- {2- [5- (2-Methoxy-ethoxy) benzimidazol-1-yl] -quinolin-8-yl} -4-methyl-piperidin-4-ylamine; 2- {1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yloxy} -ethanol; 1- [2- (5,6-Dimethoxy-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine; 1- [2- (6,7-dihydro-5,8-dioxa-1,3-diaza-cyclopenta [b] naphthalen-1-yl) -quinolin-8-yl] -piperidin-4-ylamine; (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -dimethyl-amine; (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -methyl-amine; 2- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzylamino) -ethanol; 4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl) -quinolin-8-yl} -benzylamine; 2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8- (4-pyrrolidin-1-ylmethyl-phenyl) -quinoline; 2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8- (4-pyrrolidin-1-ylmethyl-phenyl) -quinoline; 2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -8- (4-pyrrolidin-1-ylmethyl-phenyl) -quinoline; 1- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -cis-pyrrolidine-3,4-diol; R, R- (1- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -trans-pyrrolidine-3,4-diol ); 1- (4- {2- [5- (2-Methoxy-ethoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -benzyl) -pyrrolidin-3-ol; R- (1- (4- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -benzyl) -pyrrolidin-3-ol); S- (1 - (4- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -benzyl) -pyrrolidin-3-ol); 1- (4- {2- [5- (2-methoxyethoxy) benzimidazol-1-yl] quinolin-8-yl} benzyl) azetidin-3-ol; 2- [5- (2-methoxyethoxy) benzimidazole-1 -yl] -8- [4- (4-methylpiperazin-1-ylmethyl) -phenyl] -quinoline; 1- (4- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl ] -quinolin-8-yl} -benzyl) -piperidin-4-ylamine; (1- {2- [5- (2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidine (1- {2- [5- (2-methoxy-ethoxy) -benzimidazole] -quinolin-8-yl} -piperidin-4-ylmethyl) -methylamine; 2- [5- (4-yl) -methanol; 2-methoxy-ethoxy) -benzimidazol-1-yl] -8- [4- (4-methylpiperazin-1-ylmethyl) -piperidin-1-yl] -quinoline; (1- {2- [5- (2- 2-methoxy-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylmethyl) -dimethylamine; C- (1- {2- [5- (2-methoxyethoxy) -benzimidazole 1-yl] -quinolin-8-yl} -piperidin-4-yl) -methylamine; S, S- (1- (4- {2- [5- (2-methoxy-ethoxy) -benzimidazole-1-one yl] -quinoline -8-yl} -benzyl) -trans-pyrrolidine-3,4-diol); 4- {2- [5- (3-Dimethylamino-propoxy) -benzoimidazol-1-yl] -quinolin-8-yl} -phenol; 1- [2- (5-Phenyl-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine; 1- [2- (5-pyridin-4-yl-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine; 1- {2- [5- (3-Methoxy-phenyl) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; 1- [2- (5-pyridin-3-yl-benzimidazol-1-yl) -quinolin-8-yl] -piperidin-4-ylamine; 1- {2- [5- (6-methoxy-pyridin-3-yl) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; 1- {2- [5- (4-Aminomethyl-phenyl) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; 4- {1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yl} -benzoic acid methylester; 4- {1- [8- (4-Amino-piperidin-1-yl) -quinolin-2-yl] -1H-benzimidazol-5-yl} -phenol; 1 - [[2- [5- (3-morpholinoethoxy) -1H-benzimidazol-1-yl] -quinolin-8-yl]] - piperidin-4-ylamine trihydrochloride; Ethyl-1- [8- (4-aminopiperidin-1-yl) -quinolin-2-yl] -benzimidazole-5-carboxylate; N- (4-Morpholino) ethyl-1- [8- (4-aminopiperidin-1-yl) -quinolin-2-yl] -benzimidazole-5-carboxamide; 1- {2- [5- (4-Methylaminomethyl-phenyl) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; 1- {2- [5- (4-dimethylaminomethyl-phenyl) -benzoimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine; 1- (2- {2- [2- (2-Methyl-imidazol-1-yl) -ethoxy] -benzimidazol-1-yl} -quinolin-8-yl) -piperidin-4-ylamine and 1- {2 - (5- (2- [1,2,4) -triazol-1-yl-ethoxy) -benzimidazol-1-yl] -quinolin-8-yl} -piperidin-4-ylamine, and the pharmaceutically acceptable salts, Prodrugs and solvates of the compounds mentioned above. Pharmaceutical composition, a lot A compound according to claim 1 and a pharmaceutically acceptable carrier includes. A compound according to claim 1 for use as a medicament. Use of a compound according to claim 1 for Preparation of a medicament for the treatment of abnormal cell growth in a mammal. Use according to claim 18, wherein the abnormal cell growth Cancer is. The use according to claim 19, wherein the cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, colon cancer, breast cancer, uterine cancer, tubal cancer, endometrial carcinoma, Cervical carcinoma, vaginacarcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine systemic cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, renal or ureteral cancer, hypernitrophic carcinoma, renal pelvic carcinoma, central nervous system neoplasms (CNS), primary CNS lymphoma, spinal tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the aforementioned cancers is.